FACULTY RESEARCH SPOTLIGHT · 2025

Reinventing the Quantum Dot: How Quantum Shells Are Rewriting the Rules of Nanoscale Light

Mikhail Zamkov, Ph.D.  ·  Professor  ·  Department of Physics and Astronomy & Center for Photochemical Sciences

In 2023, the Nobel Prize in Chemistry was awarded to Moungi Bawendi, Louis Brus, and Aleksei Ekimov for the discovery and synthesis of quantum dots — nanoscale semiconductor crystals whose optical properties are governed not by their chemical composition alone, but by their size. Shrink a semiconductor to a few nanometers and quantum mechanical effects take over: the material begins to glow in colors that depend precisely on how small it is. The smaller the dot, the bluer the light. The Nobel committee called quantum dots "almost perfect particles."

Dr. Mikhail Zamkov, Professor of Physics and Astronomy and a member of BGSU's Center for Photochemical Sciences, has built his research career on an uncomfortable question: if quantum dots are almost perfect, what exactly is imperfect about them, and can you fix it?

The answer, his group has demonstrated over the past several years, involves a fundamental limitation called Auger recombination — a process in which the energy that should produce light instead gets transferred between charge carriers inside the nanocrystal and is lost as heat. Auger recombination is what keeps quantum dots from being used as laser gain media and limits their performance in high-intensity applications like scintillation, advanced displays, and medical imaging.

The solution Dr. Zamkov and his group have pioneered is to replace the solid quantum dot with a hollow shell — a quantum shell — in which electrons and holes are confined to a thin semiconductor shell surrounding a large inert core. This architectural change fundamentally alters how charge carriers interact with each other, dramatically suppressing Auger recombination while preserving and even enhancing the optical properties that make quantum-confined nanocrystals so compelling.

"Nanocrystals are like Lego bricks that you build your applications with. You can program whatever property you want in each one of those bricks — and then they self-assemble."

In 2025, the Zamkov Lab published four papers that collectively mark a pivotal year for quantum shell science: establishing laser performance, probing behavior under electron beam excitation, unlocking a new stimulated emission regime that breaks fundamental assumptions in the field, and contributing to a cross-group account of overcoming one of the deepest challenges in anion sensing. Notably, BGSU's Zamkov Lab is currently the only research group in the world producing these quantum shell nanocrystals.

01  Building a Printable Laser: Quantum Shells Take Aim at Lasing

Published in: Nanoscale, 17(7), 3698–3707 · January 2025

Authors: D. Nazar, A.D. Waters, M.M. Kannen, D. Harankahage, J. Huang, M. Zamkov

DOI: 10.1039/D4NR04653F

THE PROBLEM WITH QUANTUM DOT LASERS

The idea of a solution-processable laser — one that could be printed or coated onto a surface like an ink — has tantalized researchers for decades. Conventional lasers require precise crystal growth in specialized facilities; a printable laser diode would dramatically reduce costs and enable entirely new form factors, from flexible photonics to wearable sensors and low-cost fiber-optic emitters.

Quantum dots have long been viewed as the most promising platform for this vision. Their tunable bandgaps, narrow emission linewidths, and compatibility with solution processing make them ideal candidates in principle. In practice, however, the Auger recombination problem becomes acute in a lasing context. To achieve optical gain, a nanocrystal must be excited so strongly that multiple electron-hole pairs — called excitons — are generated simultaneously. But when two or more excitons coexist in a quantum dot, Auger recombination becomes fast and efficient: one exciton annihilates another, converting the optical energy to heat before it can contribute to stimulated emission. The result is high lasing thresholds and short gain lifetimes that have prevented quantum dot lasers from becoming commercially viable.

HOW QUANTUM SHELLS CHANGE THE EQUATION

This paper demonstrates how quantum shells — spherical quantum wells in which a thin CdSe shell is grown over a large CdS core — overcome this limitation for lasing applications. By distributing the exciton wavefunction across the shell volume rather than concentrating it in a solid dot, the quantum shell architecture dramatically reduces the probability of exciton-exciton interactions, which are the driver of Auger recombination.

The Nanoscale paper establishes the lasing performance of CdSe/CdS quantum shells in detail, characterizing their optical gain characteristics, amplified spontaneous emission thresholds, and gain bandwidth. The results confirm that quantum shells can sustain lasing conditions — including the simultaneous presence of multiple excitons — far more effectively than conventional quantum dots, translating directly into lower lasing thresholds and longer gain lifetimes.

For the broader field, this paper is a foundational reference: the first systematic characterization of quantum shells in a laser context, establishing the key performance metrics and demonstrating that the quantum shell architecture is a viable path to solution-processed laser diodes. The NSF, recognizing the significance of this research direction, has awarded Dr. Zamkov a grant specifically to advance quantum shell-based printable laser development — an investment that reflects both the scientific promise and the potential commercial impact of this work.

Lower thresholds. Longer gain lifetimes. A path to lasers you can print. The quantum shell changes the rules for nanocrystal lasing.

02  Electron Beams and Nanocrystals: Mapping the Limits of Cathodoluminescence

Published in: Nano Letters, 25(28), 11068–11074 · July 2025

Authors: B.T. Diroll, R. Sevik, M. Hua, J. Cassidy, D. Harankahage, M. Zamkov

DOI: 10.1021/acs.nanolett.5c02069

Collaborating Institution: Argonne National Laboratory (Center for Nanoscale Materials)

CATHODOLUMINESCENCE: A POWERFUL BUT UNDEREXPLORED TOOL

Cathodoluminescence — the emission of light when a material is struck by a beam of high-energy electrons — is one of the most powerful techniques available for characterizing the optical properties of nanoscale materials with spatial resolution at the level of individual particles, and even individual defects. In a scanning electron microscope, a focused electron beam can be scanned across a sample while the emitted light is collected, creating maps of optical emission with nanometer-scale spatial precision.

The technique has been applied successfully to many inorganic semiconductors, but its use with colloidal nanocrystals has remained limited and poorly understood. Individual reports of nanocrystal cathodoluminescence are more than a decade old, yet the field has never systematically characterized what makes some nanocrystals bright and stable under electron beam irradiation while others rapidly degrade — a phenomenon known as cathodobleaching.

WHAT THE STUDY REVEALED

This paper, a collaboration between the Zamkov group at BGSU and researchers at Argonne National Laboratory's Center for Nanoscale Materials, undertakes the first comprehensive study of cathodoluminescence from semiconductor quantum shells — CdS/CdSe/CdS structures that have already demonstrated exceptional brightness and durability under X-ray excitation (scintillation).

The results are illuminating in both senses of the word. On the positive side, the quantum shells show bright and durable radioluminescence under X-ray excitation, reaching up to 100 photons per keV — among the best reported for colloidal nanocrystals. However, under electron beam irradiation, the quantum shells are significantly less bright than under X-ray photons. The study pinpoints the cause through a systematic series of experiments varying electron beam voltage, current, dwell time, and atmospheric pressure.

The culprit is cathodobleaching from sample charging — not thermal effects or photochemical degradation as had been variously proposed. When high-energy electrons deposit charge in the sample faster than it can dissipate, the resulting electric field disrupts the optical emission. This is a materials and measurement challenge, not an intrinsic limitation of the nanocrystals themselves, and the paper identifies the specific conditions under which it occurs and how it can be mitigated.

Understanding why nanocrystals fail under an electron beam is the first step to designing materials that don't.

WHY IT MATTERS

Cathodoluminescence is emerging as an important tool for characterizing nanocrystal optoelectronic devices with nanometer resolution, and for applications like electron-beam-pumped light sources. By systematically identifying and explaining the cathodobleaching mechanism in quantum shells, this paper provides both a practical guide for researchers using cathodoluminescence to study nanocrystals, and a set of materials design criteria for developing nanocrystals that can withstand electron beam excitation — opening the door to new applications at the intersection of electron microscopy and nanophotonics.

03  Below the Bandgap: A New Frontier in Optical Gain

Published in: Journal of the American Chemical Society, 147(31), 28454–28463 · July 2025

Authors: A.D. Waters, M.V. Bondarchuk, C.M. Hicks, S. Smith, D. Nazar, M.M. Kannen, D. Harankahage, S. Thennakoon, J. Huang, E. Anzenbacher, P. Anzenbacher, A.N. Tarnovsky, A.V. Malko, M. Zamkov

DOI: 10.1021/jacs.5c09795

Collaborating Institutions: BGSU Center for Photochemical Sciences, University of Texas at Dallas

WHAT 'BELOW THE BANDGAP' MEANS — AND WHY IT SHOULDN'T BE POSSIBLE

In semiconductor physics, the bandgap is the energy gap between the valence band — where electrons normally reside — and the conduction band — where they go when excited. For a nanocrystal to emit light, an electron must fall back across this gap, releasing a photon whose energy corresponds to the bandgap energy. The rule is foundational: you cannot get stimulated emission from a material at energies below its bandgap, because there are simply no electronic transitions available at those energies.

Except, as this paper demonstrates, quantum shells can break that rule.

This is the most striking finding of the Zamkov Lab's 2025 output — a result important enough to land in the Journal of the American Chemical Society, chemistry's most prestigious journal. The paper demonstrates stimulated emission from giant colloidal quantum shells (g-QSs) — structures comprising a quantum-confined CdSe shell grown over a large, approximately 14-nanometer CdS bulk core — at energies both above and, remarkably, below the bandgap.

THE PHYSICS BEHIND THE DISCOVERY

The giant quantum shell architecture is key. The large CdS core functions as a bulk semiconductor, while the thin CdSe shell provides quantum confinement. Because the CdS core is so large, exciton-exciton interactions within the structure are dramatically reduced — so Auger recombination is strongly suppressed. This suppression is the prerequisite for everything that follows.

With Auger recombination out of the way, the quantum shells can sustain multiexciton states for long enough that stimulated emission becomes possible. And because of the unusual electronic structure created by the bulk-nanoscale architecture — the interaction between the quantum-confined shell states and the bulk-like core states — the gain bandwidth is extraordinarily broad, spanning not just the energy region above the formal bandgap, but extending below it as well.

The sub-bandgap gain arises from bound multiexciton complexes — clusters of charge carriers whose collective states fall at energies lower than the nominal single-exciton transition. This is a quantum mechanical effect enabled by the specific architecture of the giant shell: the large core provides room for multiple excitons to coexist and interact in ways that create new effective optical transitions.

The result is one of the broadest gain bandwidths ever reported for any colloidal nanomaterial — a finding that the BGSU team confirmed using ultrafast spectroscopy techniques, with Dr. Alexander Tarnovsky and graduate students contributing the time-resolved optical characterization essential to establishing the gain mechanism. Dr. Pavel Anzenbacher also contributed, and notably his son Edison Anzenbacher — a BGSU undergraduate — is listed as a co-author, a remarkable contribution from an early-career researcher.

Stimulated emission from below the bandgap: a result that should be impossible — until you build a nanocrystal whose architecture rewrites the rules of what's possible.

APPLICATIONS AND IMPACT

The implications of sub-bandgap optical gain in quantum shells are broad. In conventional semiconductor laser design, gain bandwidth is constrained by the material's electronic structure. A gain medium that operates below its own bandgap effectively functions at longer wavelengths than the material's intrinsic emission — meaning that a CdSe/CdS quantum shell system could, in principle, produce laser output at wavelengths that neither CdSe nor CdS would normally reach. This opens entirely new spectral windows for solution-processed lasers without requiring new materials.

The paper also reinforces a central thesis of the Zamkov group's research program: that the quantum shell architecture, by fundamentally altering how charge carriers are confined and interact, enables optical phenomena that are simply unavailable in conventional quantum dots. The discovery of sub-bandgap gain is the most dramatic demonstration of this to date, and it suggests that the full landscape of quantum shell capabilities has not yet been mapped.

04  Across Disciplines: Overcoming the Water Problem in Anion Sensing

Published in: Accounts of Chemical Research, 58(17), 2792–2803 · August 2025

Authors: P. Anzenbacher Jr., S. George, A. Prakash, A. Sartori, M. Zamkov, A.N. Tarnovsky

DOI: 10.1021/acs.accounts.5c00472

THE DEEPEST CHALLENGE IN ANION SENSING

Designing artificial receptors that can selectively bind and detect anions — negatively charged species like phosphate, sulfate, nitrate, and a host of biologically and environmentally relevant molecules — is one of the central problems in supramolecular chemistry. Such receptors have applications ranging from detecting agricultural runoff and chemical weapons precursors to monitoring cellular biochemistry and developing new drugs.

But water makes it extraordinarily hard. Water molecules form strong hydrogen bonds with anions, surrounding them with a hydration shell that must be stripped away before any artificial receptor can bind them. Most synthetic receptors bind anions well in organic solvents, where solvation is weaker — but in water, the thermodynamic cost of displacing those water molecules overwhelms the binding energy. The result is that even very well-designed receptors perform poorly in aqueous environments, which is exactly where they need to work for most real-world applications.

THE BIOMIMETIC SOLUTION

This paper, published in Accounts of Chemical Research — the journal that invites leading researchers to write personal accounts of their group's contributions to a field — presents the Anzenbacher group's decade-spanning program to solve this problem by taking inspiration from biology.

Enzymes and proteins solve the water problem routinely. They bind anions and other charged guests in water with exquisite selectivity by using shaped binding pockets that combine enthalpic interactions (hydrogen bonds, electrostatics) with entropic effects (desolvation — the release of ordered water molecules from both the guest and the binding site, which increases entropy and drives binding). Most synthetic receptor design has focused on the enthalpic side; this program argues that deliberately designing for the entropic component — solvation and desolvation — is the key to building receptors that actually work in water.

Dr. Zamkov's contribution to this Account comes through the group's use of advanced spectroscopic characterization and materials understanding to support the development and validation of the receptor systems. The collaboration — spanning Anzenbacher's supramolecular chemistry expertise, Tarnovsky's ultrafast spectroscopy capabilities, and Zamkov's nanomaterials and optical characterization strengths — exemplifies the kind of cross-disciplinary research that the Center for Photochemical Sciences is uniquely positioned to enable.

Biology solves the water problem every day. The question is how to teach that lesson to synthetic chemistry.

WHY IT MATTERS

The Accounts of Chemical Research format — a reflective, synthesizing overview of a research program's contributions — means this paper both summarizes and contextualizes years of work. For the anion sensing field, it provides a coherent intellectual framework for why the biomimetic, entropy-focused approach succeeds where conventional enthalpic design falls short. For the Center for Photochemical Sciences, it is a demonstration of the collaborative science that defines the institution: three CPS faculty members — Anzenbacher, Tarnovsky, and Zamkov — contributing different expertise to a single, coherent research program published in one of chemistry's most respected venues.

A UNIFIED RESEARCH VISION

The Quantum Shell Program: From Fundamental Physics to Real-World Impact

Four papers across four different journals — Nanoscale, Nano Letters, the Journal of the American Chemical Society, and Accounts of Chemical Research — tell a story about a research program hitting its stride. The quantum shell platform that Dr. Zamkov's group has been building for years is now producing results at the highest levels of scientific significance, and the downstream applications are coming into focus.

The lasing paper establishes quantum shells as a viable gain medium for printable lasers. The cathodoluminescence paper maps their behavior under electron beam excitation and identifies the conditions under which their extraordinary optical properties hold up — and where they need improvement. The JACS paper reveals that quantum shells can produce optical gain at energies that no one expected, opening spectral windows that conventional quantum dots cannot reach. And the Accounts paper demonstrates that the Zamkov Lab's expertise extends beyond nanocrystal physics, contributing to cross-cutting collaborative research that addresses one of the oldest challenges in synthetic chemistry.

Running through all of this is the quantum shell's central innovation: suppressed Auger recombination. By distributing charge carriers across a shell rather than concentrating them in a dot, the Zamkov Lab has engineered away the most fundamental obstacle to using nanocrystals in high-performance photonic devices. The 2025 publications show what becomes possible when that obstacle is removed — and point toward applications in lasers, displays, scintillators, medical imaging, and chemical sensing that are no longer speculative.

Graduate students Divesh Nazar, Amelia Waters, Dulanjan Harankahage, Mykhailo Bondarchuk, Christopher Hicks, Maxwell Kannen, Siddhartha Thennakoon, Jiamin Huang, and James Cassidy are central contributors to this body of work. Their combined experimental expertise — in colloidal synthesis, optical spectroscopy, electron microscopy, and device characterization — is what makes the quantum shell program possible, and what ensures that its scientific advances will continue well into the future.

As the Center for Photochemical Sciences celebrates 40 years, the Zamkov Lab stands as a reminder that the center's tradition of frontier photophysics research is very much alive — and that some of its most consequential work is still being written.

2025 Publications — Zamkov Laboratory

Nazar, D., Waters, A.D., Kannen, M.M., Harankahage, D., Huang, J., & Zamkov, M. (2025). Colloidal Semiconductor Quantum Shells for Solution-Processed Laser Applications. Nanoscale, 17(7), 3698–3707. https://doi.org/10.1039/D4NR04653F

Diroll, B.T., Sevik, R., Hua, M., Cassidy, J., Harankahage, D., & Zamkov, M. (2025). Evaluating Brightness and Stability of Cathodoluminescence from Colloidal Semiconductor Nanocrystals. Nano Letters, 25(28), 11068–11074. https://doi.org/10.1021/acs.nanolett.5c02069

Waters, A.D., Bondarchuk, M.V., Hicks, C.M., Smith, S., Nazar, D., Kannen, M.M., Harankahage, D., Thennakoon, S., Huang, J., Anzenbacher, E., Anzenbacher, P., Tarnovsky, A.N., Malko, A.V., & Zamkov, M. (2025). Stimulated Emission from Below the Bandgap in Giant Quantum Shells. Journal of the American Chemical Society, 147(31), 28454–28463. https://doi.org/10.1021/jacs.5c09795

Anzenbacher, P., Jr., George, S., Prakash, A., Sartori, A., Zamkov, M., & Tarnovsky, A.N. (2025). Overcoming the Hydration and Solvation Problem in Ion Recognition and Binding: The Biomimetic Approach. Accounts of Chemical Research, 58(17), 2792–2803. https://doi.org/10.1021/acs.accounts.5c00472

For more about Dr. Zamkov's research, visit physics.bgsu.edu/~zamkovm  or  bgsu.edu/arts-and-sciences/center-for-photochemical-sciences/ResearchFaculty/mikhail-zamkov

FACULTY RESEARCH SPOTLIGHT · 2025

Beyond Antibodies: Aptamers as the Next Generation of Precision Molecular Targeting

Xiaohong Tan, Ph.D.  ·  Assistant Professor  ·  Department of Chemistry & Center for Photochemical Sciences

Antibodies are the workhorses of modern medicine. From cancer immunotherapy to diagnostic testing, these large Y-shaped proteins have become indispensable tools because of one core capability: the ability to recognize a specific molecular target — a protein on a cancer cell, a viral coat protein, a toxin — with extraordinary precision, and to bind to it tightly enough to matter.

But antibodies have limitations that have frustrated researchers and clinicians for decades. They are expensive and time-consuming to produce, requiring animal hosts or complex cell culture systems. They are large, which restricts their ability to penetrate tumors and tissues. They can trigger immune responses in patients. They are fragile, requiring cold storage. And perhaps most importantly, their ability to be chemically modified — decorated with drugs, detection probes, or other functional groups — is limited and technically demanding.

Enter aptamers: short, single-stranded DNA or RNA molecules that can fold into precise three-dimensional structures and bind to specific targets with affinity and selectivity that rival, and sometimes exceed, antibodies. Aptamers are selected from vast molecular libraries through a process called SELEX — Systematic Evolution of Ligands by Exponential Enrichment — that mimics Darwinian selection at the molecular scale: rounds of binding, washing, and amplification converge on sequences that cling to their target with increasing tenacity.

The advantages are compelling. Aptamers are synthesized chemically, not biologically, making them reproducible, scalable, and inexpensive to produce. They are thermally stable and can be stored at room temperature. They are small enough to penetrate tissues where antibodies cannot. They can be chemically modified with almost any functional group imaginable. And the SELEX process itself can be engineered with remarkable creativity to find aptamers that do things antibodies cannot — like binding to two different sites on the same protein simultaneously, or targeting the active machinery of a dangerous pathogen.

Aptamers are the chemical antibodies that chemists can actually engineer — small, stable, precise, and infinitely modifiable.

Dr. Xiaohong Tan, Assistant Professor in BGSU's Department of Chemistry and the Center for Photochemical Sciences, has built his research program around the development and application of DNA aptamers for problems at the intersection of cancer biology, infectious disease, and chemical biochemistry. His 2025 publications address two of the most pressing challenges in these fields: how to make cancer immunotherapy more effective by targeting a key immune checkpoint protein with unprecedented sophistication, and how to develop tools for studying and combating one of the most dangerous antibiotic-resistant pathogens in clinical medicine.

01  Targeting Cancer's Shield: Dual-Site Aptamers Against PD-L1

Published in: ACS Biomaterials Science & Engineering, 11(8), 5085–5095 · 2025

Authors: A.P. Silwal, S.K.S. Thennakoon, R. Jahan, S.P. Arya, R.M. Postema, H.P. Timilsina, A.M. Reynolds, K.B. Kokensparger, X. Tan

DOI: 10.1021/acsbiomaterials.4c02053

THE CHECKPOINT PROBLEM IN CANCER IMMUNOTHERAPY

One of the most transformative developments in cancer medicine over the past decade has been immune checkpoint therapy — the use of drugs that remove molecular "brakes" that tumors use to hide from the immune system. When a cancer cell displays a protein called PD-L1 (Programmed Death-Ligand 1) on its surface, it sends a signal to nearby immune T cells to stand down, suppressing the immune attack that would otherwise destroy the tumor. Drugs that block the interaction between PD-L1 and its receptor PD-1 — including the blockbuster cancer drugs pembrolizumab and atezolizumab — have produced remarkable clinical results in some cancers, prolonging survival in patients with lung cancer, melanoma, and other malignancies.

These drugs are antibodies. They work by physically blocking PD-L1, preventing it from delivering its immunosuppressive signal. But they have shortcomings. They are expensive to manufacture, can cause significant immune side effects as the unleashed immune system attacks healthy tissue as well as cancer, and do not work for all patients or all cancer types. The search for better, more precise tools to target PD-L1 — ones that can be engineered with greater sophistication and deployed more flexibly — is an active area of research worldwide.

One particularly promising strategy is the development of heterobivalent fusion aptamers: aptamers that bind to two different sites on the PD-L1 protein simultaneously, grasping the target from two directions at once. This approach is expected to dramatically increase binding affinity (since releasing the target requires both sites to let go simultaneously), offer more complete blockade of PD-L1 function, and potentially provide access to functional effects that a single-site binder cannot achieve. The obstacle has been technical: finding two aptamers that both bind to the same protein but at distinct, non-overlapping sites has been a significant challenge with conventional SELEX methods.

THE AADS INNOVATION

This paper introduces and validates Aptamer-Assisted DNA SELEX (AADS), a novel selection strategy designed specifically to solve this problem. The approach is elegant in its logic. First, a conventional SELEX campaign against PD-L1 yields Aptamer 1 — in this case, the aptamer designated P1C2, which binds to a specific site on PD-L1 with high affinity. Then, rather than starting a second SELEX campaign against bare PD-L1, the team performs a second selection against the PD-L1/P1C2 complex: PD-L1 with Aptamer 1 already sitting in its binding site. By selecting against this pre-occupied target, the second SELEX round is forced to find aptamers that bind somewhere else on the protein — somewhere that Aptamer 1 is not blocking.

The result is Aptamer 2, designated P1CSC, which recognizes a distinct region of PD-L1 simultaneously accessible when P1C2 is bound. After confirming that both aptamers can indeed bind PD-L1 at the same time — a critical validation step — the team engineered fusion aptamers: single molecules that contain both binding sequences connected by optimized linker sequences. Through systematic optimization of linker length and orientation, they arrived at the optimized fusion aptamer P1CSC-T7-P1C1, a single DNA molecule capable of grasping PD-L1 at two sites in one binding event.

AADS turns the selection process itself into a precision tool — using the first aptamer as a molecular mask to force the second selection toward an unoccupied site.

WHY IT MATTERS

The AADS strategy solves a fundamental problem in aptamer engineering: how to find two aptamers that bind the same protein without competing with each other. This is not merely a technical achievement — it opens up an entirely new design space for therapeutic and diagnostic aptamers. Fusion aptamers that bind two sites simultaneously are expected to have dramatically enhanced binding affinity compared to single-site binders, greater resistance to displacement by competing molecules, and potentially the ability to block protein-protein interactions more completely.

For PD-L1 specifically, a fusion aptamer that grips the protein from two directions has clear potential as a next-generation cancer immunotherapy agent — one that could compete with antibody-based checkpoint inhibitors while offering the advantages of aptamers: lower cost, better tissue penetration, easier chemical modification, and the ability to be conjugated with drugs or imaging agents for theranostic applications.

Beyond this specific application, AADS represents a generalizable methodology that other researchers can apply to any protein target where multi-site engagement is desired. The paper establishes the proof of concept on a clinically highly relevant target, providing both the technical framework and the biological validation needed for the field to adopt and extend this approach.

02  Targeting the Enemy's Engine: Aptamers Against P. aeruginosa RNA Polymerase

Published in: Chemical Communications, 61(25), 4848–4851 · March 2025

Authors: H. Timilsina, D. Kompaniiets, S.P. Arya, R.M. Postema, R. Jahan, A.M. Reynolds, S.K.S. Thennakoon, B. Liu, X. Tan

DOI: 10.1039/D5CC00682A

Collaborating Institution: The Hormel Institute, University of Minnesota

A PATHOGEN THAT DEFEATS ANTIBIOTICS

Pseudomonas aeruginosa is one of the most feared pathogens in clinical medicine. A Gram-negative bacterium found in soil, water, and hospital environments, P. aeruginosa causes life-threatening infections in immunocompromised patients, burn victims, and people with cystic fibrosis. What makes it so dangerous is not just its ability to infect diverse tissues — lungs, wounds, blood, urinary tract — but its extraordinary capacity to resist antibiotics. P. aeruginosa employs multiple resistance mechanisms simultaneously: efflux pumps that expel antibiotics before they can act, enzymes that chemically inactivate drugs, and the ability to form biofilms — dense communities of bacteria encased in a protective matrix that antibiotics struggle to penetrate.

The World Health Organization has classified P. aeruginosa as one of its "Priority 1" critical pathogens, meaning it poses the greatest threat to human health and represents an urgent unmet need for new therapies. As existing antibiotics lose effectiveness against increasingly resistant strains, the need for fundamentally new approaches to targeting this bacterium has never been more acute.

A NEW KIND OF TARGET: RNA POLYMERASE

Most antibiotics target fundamental bacterial processes — cell wall synthesis, protein synthesis, DNA replication, or membrane integrity. Relatively few target the bacterial transcription machinery: the RNA polymerase (RNAP) that reads the bacterial genome and produces the messenger RNA that bacteria need to make proteins and carry out all cellular functions. RNAP is, in a sense, the master coordinator of bacterial gene expression — the machine without which a bacterium cannot respond to its environment, regulate its virulence factors, or adapt to stress.

RNAP is an established antibiotic target in some bacteria — the drug rifampicin works by binding bacterial RNAP — but for P. aeruginosa, no aptamers had ever been developed to target its RNAP. This is partly because obtaining enough purified P. aeruginosa RNAP for experimental work is itself technically challenging, and partly because the biological tools needed to study RNAP function in this pathogen have lagged behind those available for better-studied organisms.

THE FIRST P. AERUGINOSA RNAP APTAMERS

This paper presents the first DNA aptamers designed to target the RNA polymerase of Pseudomonas aeruginosa — a genuinely novel reagent for a critically important pathogen. Using SELEX against purified P. aeruginosa RNAP, the Tan Lab identified a panel of candidate aptamers and subjected them to rigorous characterization. Among these, the aptamer designated R2 emerged as the standout: it demonstrated high specificity for P. aeruginosa RNAP and significant binding affinity, distinguishing the target enzyme from non-target proteins with the selectivity that makes a useful research or therapeutic tool.

Critically, R2 was also shown to be functional in practical applications. The aptamer could effectively capture P. aeruginosa RNAP in protein tandem purification experiments — binding the enzyme from complex mixtures and allowing it to be isolated — and could be used in coating applications, providing a surface-bound capture agent for RNAP. These demonstrations establish R2 as a versatile research reagent with immediate utility for studying P. aeruginosa transcription biology, and lay the groundwork for more ambitious downstream applications.

The first aptamers ever developed against P. aeruginosa RNAP — opening a new molecular toolkit for studying and targeting one of medicine's most dangerous pathogens.

WHY IT MATTERS

The significance of this paper operates at multiple levels. At the most immediate level, R2 and its companion aptamers are new research tools for the scientific community studying P. aeruginosa biology — tools that have not existed before. Understanding how P. aeruginosa regulates gene expression, including the expression of virulence factors, antibiotic resistance genes, and biofilm formation programs, is central to understanding how this bacterium causes disease. Aptamers that capture and detect RNAP provide a new handle on those questions.

At a more forward-looking level, aptamers that bind bacterial RNAP with high specificity are potential starting points for a new class of anti-Pseudomonas agents. An aptamer that binds RNAP tightly enough could potentially inhibit transcription, blocking the bacterium's ability to respond to its environment and express the factors it needs to infect and persist. Given the urgent need for new antibacterials against P. aeruginosa — particularly ones that work through novel mechanisms that existing resistance would not immediately counter — this represents a scientifically significant direction.

The collaboration with the Liu group at the Hormel Institute, University of Minnesota, reflects the kind of cross-institutional partnership that advances work of this nature — combining the Tan Lab's aptamer selection and engineering expertise with the Hormel Institute's focus on transcription and gene regulation to tackle a problem that neither team could address alone.

A UNIFIED RESEARCH VISION

Aptamers as Precision Tools Across Biology's Hardest Problems

Two papers, two very different biological targets, two very different clinical challenges — but one coherent scientific program. The unifying thread through both of Dr. Tan's 2025 publications is a commitment to pushing the technical and conceptual boundaries of what aptamers can do, and applying that expanded capability to problems where conventional molecular tools have fallen short.

The AADS paper addresses cancer immunotherapy, one of medicine's most active frontiers, by solving a fundamental problem in aptamer engineering that had resisted solution with conventional methods. The result is not just a set of useful reagents for PD-L1 research — it is a new methodology that any aptamer laboratory can adopt to develop dual-site binders against any protein of interest. The conceptual contribution may prove as significant as the specific aptamers produced.

The P. aeruginosa RNAP paper addresses antibiotic resistance, one of medicine's most urgent crises, by creating tools that did not exist before. First-in-class aptamers against a pathogen's central transcription machinery represent both immediate research utility and a long-term trajectory toward novel antimicrobial strategies. In a field where the pipeline of new antibiotics has been worryingly thin for decades, new molecular approaches to targeting bacterial gene expression machinery represent a genuinely important direction.

Graduate and undergraduate students in the Tan Lab — including Achut Prasad Silwal, Siddhartha Kalpa Samadhi Thennakoon, Raunak Jahan, Satya Prakash Arya, Rick Mason Postema, Hari Prasad Timilsina, Andrew Michael Reynolds, and Kaytelee Brooke Kokensparger — are central contributors to both papers, reflecting the lab's investment in student training across the full arc of a research project: from molecular selection through characterization and functional validation.

Dr. Tan joined BGSU's faculty in 2020 and has rapidly established a research identity at the intersection of chemical biology, nucleic acid chemistry, and translational medicine. His 2025 publications demonstrate a program that is both technically rigorous and strategically focused on problems where the aptamer platform's unique advantages can make a genuine difference. As the Center for Photochemical Sciences marks its 40th anniversary, the Tan Lab represents the center's continued vitality in recruiting and supporting emerging investigators whose work connects the fundamentals of molecular recognition to real-world biological and medical impact.

2025 Publications — Tan Laboratory

Silwal, A.P., Thennakoon, S.K.S., Jahan, R., Arya, S.P., Postema, R.M., Timilsina, H.P., Reynolds, A.M., Kokensparger, K.B., & Tan, X. (2025). Aptamer-Assisted DNA SELEX: Dual-Site Targeting of a Single Protein. ACS Biomaterials Science & Engineering, 11(8), 5085–5095. https://doi.org/10.1021/acsbiomaterials.4c02053

Timilsina, H., Kompaniiets, D., Arya, S.P., Postema, R.M., Jahan, R., Reynolds, A.M., Thennakoon, S.K.S., Liu, B., & Tan, X. (2025). DNA Aptamers Targeting P. aeruginosa RNAP. Chemical Communications, 61(25), 4848–4851. https://doi.org/10.1039/D5CC00682A

For more about Dr. Tan's research, visit bgsu.edu/arts-and-sciences/chemistry/faculty/Xiaohong-Tan

FACULTY RESEARCH SPOTLIGHT · 2025

What Happens After the Flash: Reading the Invisible Pathways of Photochemical Reactions

Jayaraman Sivaguru, Ph.D.  ·  Distinguished University Professor  ·  Associate Director, Center for Photochemical Sciences
 Alexander N. Tarnovsky, Ph.D.  ·  Associate Professor  ·  Department of Chemistry & Center for Photochemical Sciences

When a molecule absorbs a photon of light, everything that happens next takes place in a realm invisible to the naked eye and almost inconceivably fast. Within femtoseconds — millionths of a billionth of a second — electrons rearrange, bonds flex and twist, the molecule hurtles along paths on quantum mechanical energy landscapes, and either a chemical reaction occurs or the absorbed energy is harmlessly released. The entire drama plays out before a human blink has even begun.

Understanding what happens in that ultrafast window — which pathways the molecule takes, how fast, and why — is one of the central challenges of modern photochemistry. It matters enormously, because photochemical reactions drive some of biology's most important processes (vision, photosynthesis, DNA repair), power industrial applications from photolithography to drug synthesis, and underpin a growing class of precision light-driven synthetic strategies. But the transient states that carry the molecule from its initial excited form to its final products exist for only picoseconds or femtoseconds, and they cannot be observed with ordinary chemical methods.

At BGSU's Center for Photochemical Sciences, two faculty members have built research programs that approach this challenge from complementary directions — and whose collaboration produces a uniquely complete picture of photochemical reactivity that neither could achieve alone.

Dr. Jayaraman Sivaguru, Distinguished University Professor and Associate Director of the CPS, designs and synthesizes molecules with precisely controlled photochemical properties, deploying the tools of organic synthesis and photochemistry to create reactions that are stereoselective, catalytic, and tunable. His laboratory is particularly celebrated for work on atropisomeric systems — molecules whose three-dimensional shape is locked by restricted bond rotation — and on how that shape dictates the outcome of photochemical reactions with remarkable control over stereochemistry.

Dr. Alexander Tarnovsky, Associate Professor in Chemistry and a CPS member, runs one of BGSU's most technically specialized laboratories: a femtosecond transient absorption spectroscopy facility capable of capturing molecular events on timescales as short as tens of femtoseconds. His group's expertise lies in probing the ultrafast excited-state dynamics of molecules — characterizing the electronic states they pass through, the timescales on which they evolve, and the spectroscopic signatures that distinguish one pathway from another.

Sivaguru makes the molecules and designs the reactions. Tarnovsky watches what happens in the first trillionths of a second. Together, they read the full story.

Their 2025 collaborative publications reveal what that partnership can achieve: a rigorous, mechanistically complete account of how maleimide chromophores behave when struck by light, and a window into a newly discovered class of photochemical reactivity in molecules called β-enaminones — a finding with broad implications for understanding how organic molecules undergo light-driven transformations.

01  Minor Pathways, Major Consequences: The Maleimide Story

Published in: Journal of Physical Chemistry A, 129(17), 3876–3885 · May 1, 2025

Authors: D. Garg, A.N. Tarnovsky, J. Sivaguru

DOI: 10.1021/acs.jpca.5c01860

WHY MALEIMIDES MATTER

Maleimides are a class of cyclic organic compounds built around a five-membered ring containing two nitrogen-flanked carbonyl groups and a carbon-carbon double bond — the reactive site that makes them so useful in chemistry and biology. In synthetic chemistry, maleimides undergo [2+2] photocycloaddition reactions: under light, the double bond of one maleimide molecule can react with the double bond of an alkene partner, forming a four-membered ring with precise control over stereochemistry. The Sivaguru Lab has developed this chemistry extensively, particularly using atropisomeric maleimides — molecules whose restricted rotation around a C–N bond creates a chiral axis — to achieve stereospecific photocycloadditions with near-perfect enantioselectivity.

In bioconjugation chemistry, maleimides are among the most widely used functional groups for attaching molecules to proteins and other biomolecules — a billion-dollar technology base used in the production of antibody-drug conjugates for cancer treatment, among other applications. Understanding how maleimides behave in their excited states is therefore not merely of academic interest: it has direct relevance to designing more efficient and selective photochemical reactions, and to understanding how the maleimide functional group behaves under photochemical conditions in biological environments.

THE PUZZLE: WHEN A SUBSTITUENT CHANGES EVERYTHING

The immediate catalyst for this study was a puzzling observation: N-phenyl maleimide — the parent compound — readily undergoes [2+2] photocycloaddition with alkene partners when irradiated. But introduce a hydroxyl (–OH) group at the right position on the N-phenyl ring, and the photocycloaddition stops. The hydroxy-substituted maleimide, under direct irradiation conditions that work perfectly for the parent compound, simply does not react with alkenes. Why?

The answer required ultrafast spectroscopy. The Tarnovsky Lab applied femtosecond transient absorption spectroscopy — using a 355 nm pump laser pulse to excite the hydroxy-substituted maleimide and a broadband probe spanning the deep UV through near-IR — to directly observe the excited-state dynamics of the molecule in real time. For comparison, the same measurements were performed on the parent N-phenyl maleimide, excited at 350 nm.

WHAT THE ULTRAFAST MEASUREMENTS REVEALED

Both the hydroxy-substituted and the parent maleimide share a key feature: very short excited-state lifetimes driven by radiationless vibronic deactivation. This is the dominant relaxation pathway — the molecule absorbs light, reaches an excited state, and almost immediately falls back to the ground state without doing any chemistry. This internal conversion is so fast that it effectively competes with the [2+2] photocycloaddition pathway, explaining why maleimide photoreactions require careful optimization of conditions to achieve useful yields.

But for the hydroxy-substituted maleimide, the transient absorption measurements revealed something additional: a very minor pathway, distinct from the dominant deactivation channel, with spectral and kinetic signatures consistent with an excited-state proton transfer (ESPT) reaction. Excited-state proton transfer — in which a proton moves from one part of a molecule to another in the excited electronic state — is a well-known phenomenon in certain chromophores, but its presence in maleimides had not been documented before.

The critical insight is in the title: minor pathways have major implications. The ESPT pathway, even though it represents only a small fraction of the total excited-state population, diverts molecules away from the [2+2] reactive pathway. When the excited molecule undergoes proton transfer instead of proceeding toward cycloaddition, it cannot form the cyclobutane product — and that is why the hydroxy-substituted maleimide appears unreactive under direct irradiation conditions.

A pathway that accounts for only a tiny fraction of molecules can still determine the entire outcome of a reaction — by siphoning reactants away from the productive channel before they have a chance to react.

WHY IT MATTERS

This study is a paradigm case for why mechanistic understanding through ultrafast spectroscopy is essential to rational photochemical design. Without femtosecond measurements, the hydroxy-substituted maleimide would simply appear "unreactive" — a dead end. With them, the reason for the lack of reactivity is revealed: a minor but consequential excited-state proton transfer pathway that was invisible to conventional photochemical characterization.

For the Sivaguru Lab's broader program in maleimide photochemistry, this finding has immediate practical implications. If the ESPT pathway can be suppressed — through solvent choice, structural modification, or photocatalytic conditions — the hydroxy-substituted maleimide may become reactive again, with its hydroxyl group then available for further synthetic manipulation. And more broadly, the study establishes that substituents on the N-aryl group of maleimides can introduce new photophysical channels that fundamentally alter reactivity — a design principle that must be taken into account in the increasingly sophisticated photocatalytic frameworks that Sivaguru's group is developing.

02  A New Reaction, Deciphered: The β-Enaminone Discovery

Published online: Angewandte Chemie International Edition · November 17, 2025

Authors: L.M. Obloy, L.K. Valloli, A. Blanco Gonzalez, D. Garg, M.S. Bezabih, M. Olivucci, A.N. Tarnovsky, J. Sivaguru

DOI: 10.1002/anie.202519037

Collaborating Institution: University of Siena (Olivucci group)

AN UNEXPECTED REACTIVITY — AND THE NEED TO EXPLAIN IT

β-enaminones are a class of bifunctional organic molecules containing both an enamine (a carbon-nitrogen double bond conjugated with a carbon-carbon double bond) and a carbonyl group in a specific geometric arrangement. They appear widely in natural products and pharmaceuticals and have long been studied as synthetic intermediates. Their thermal chemistry is well established. Their photochemistry, however, has remained far less explored — and recent experimental work from the Sivaguru Lab revealed a photochemical transformation in β-enaminones that had not been previously documented, producing products that could not be explained by known excited-state mechanisms.

That discovery created both an opportunity and an obligation: a new photochemical reaction, confirmed experimentally, with no mechanistic explanation. Understanding what the molecule actually does in its excited state — which pathway it takes, through which electronic states, on what timescale — required the full combined arsenal of the Sivaguru, Tarnovsky, and Olivucci groups.

THREE GROUPS, ONE MECHANISM

The paper brings together three complementary methodologies in an unusually integrated collaboration. The Sivaguru group provided the synthetic chemistry — preparing the β-enaminone substrates and characterizing the photoproducts to establish what reaction is occurring. The Tarnovsky group applied femtosecond transient absorption spectroscopy to directly observe the excited-state dynamics of the β-enaminone in solution, capturing the spectroscopic signatures of the states the molecule passes through and the timescales on which it evolves. The Olivucci group contributed multistate multiconfigurational quantum chemical calculations — the same high-level computational photochemistry methods used in the group's rhodopsin work — to map the potential energy surfaces and identify the structural features that govern the reaction.

The result is a comprehensive mechanistic account. The photochemical reaction of β-enaminones proceeds through an excited-state proton transfer (ESPT) process — a previously undocumented pathway for this class of molecules. The ESPT is not a simple event; the study reveals that it is structurally and dynamically gated, meaning that the proton transfer only occurs when the molecule reaches a specific structural configuration, and that it happens in the ultrafast time domain, within femtoseconds to picoseconds of light absorption.

The full mechanistic picture is strikingly complex: the molecule progresses along three potential energy surfaces — three different electronic states — featuring two conical intersections (points where two energy surfaces touch, enabling ultrafast non-radiative transitions) and a singlet-triplet crossing. This multi-surface, multi-intersection pathway is characteristic of complex organic photochemistry, and its detailed characterization here provides a new entry in the catalog of how molecules navigate their excited-state landscapes.

Three potential energy surfaces. Two conical intersections. A singlet-triplet crossing. An undocumented proton transfer. This is what happens to a β-enaminone in the first trillionths of a second after it absorbs light.

THE ROLE OF CONICAL INTERSECTIONS

Conical intersections — the points in molecular geometry space where two electronic potential energy surfaces become degenerate — are central to modern photochemistry. They provide the "funnels" through which excited molecules rapidly decay to the ground state, and the topology of these funnels determines both the rate and the outcome of photochemical reactions. Identifying conical intersections computationally requires the high-level multiconfigurational quantum chemistry that the Olivucci group specializes in, and correlating those computational structures with the spectroscopic features observed by the Tarnovsky group is what makes the mechanistic account complete and reliable.

The discovery that β-enaminone photochemistry involves two conical intersections and a singlet-triplet crossing is itself a significant finding: it explains why the excited-state dynamics observed by ultrafast spectroscopy show complex, multi-exponential behavior rather than simple single-step relaxation, and it provides the structural basis for why the ESPT pathway in β-enaminones has the specific kinetic and spectroscopic signatures that the Tarnovsky group measured.

WHY IT MATTERS

The implications of this work are several. Most directly, it establishes the mechanism of a genuinely new photochemical reaction — one that expands the known repertoire of β-enaminone chemistry and opens new synthetic possibilities for molecules in this structural class. β-enaminones appear in numerous pharmaceutically relevant frameworks, and the ability to use light to drive their transformation through a well-understood mechanism creates opportunities for new synthetic routes to complex natural products and drug candidates.

More broadly, the paper demonstrates the power of the CPS collaborative model: synthetic photochemistry (Sivaguru), ultrafast spectroscopy (Tarnovsky), and computational photochemistry (Olivucci) working together on a single mechanistic question, each making contributions that the others cannot. The combination produces a level of mechanistic understanding that no single approach could achieve — and that is precisely the kind of science that the Center for Photochemical Sciences was built to enable. That all three groups are within the same institution, sharing students and infrastructure and a culture of collaboration, is what makes this level of integration possible.

A UNIFIED RESEARCH VISION

Seeing What Others Miss: The Sivaguru-Tarnovsky Partnership

Two papers, one shared graduate student (Dipti Garg, whose work appears in both), and a single organizing principle: the conviction that photochemical reactions can only be fully understood when synthesis, mechanistic photochemistry, and ultrafast spectroscopy are brought into direct dialogue.

Dr. Sivaguru's broader research program — encompassing atropisomeric photocycloadditions, organo-photocatalysis, supramolecular photochemistry, and light-responsive materials derived from biomass — has produced some of the most precise and selective photochemical transformations in the literature. His recent recognition as the 48th William J. Probst Memorial Lecturer, a distinction shared with Nobel laureates, reflects the field's assessment of his contributions. His NSF-funded research on photochemical reactions using visible light, with applications spanning pharmaceuticals, manufacturing, and agriculture, continues to expand the frontier of what light-controlled organic chemistry can achieve.

Dr. Tarnovsky's program provides what synthetic photochemistry cannot see on its own: the real-time dynamics of the excited states that determine why reactions proceed as they do. His femtosecond broadband transient absorption setup — covering wavelengths from the deep ultraviolet through the near-infrared, with time resolution measured in tens of femtoseconds — is one of BGSU's most technically sophisticated research instruments, and the expertise his group has developed in analyzing complex multi-state dynamics is a resource for the entire CPS community.

Graduate student Dipti Garg's central role in both 2025 publications — as lead author on the maleimide paper and a key contributor to the β-enaminone study — exemplifies the kind of student development that defines these laboratories. Working at the intersection of synthetic photochemistry and ultrafast spectroscopy, Garg has developed a rare combination of skills that positions her for leadership in the field. Graduate students Laura Obloy, Lakshmy Kannadi Valloli, and Meseret Simachew Bezabih also contributed centrally to the β-enaminone work, alongside collaborators from the Olivucci group at Siena and BGSU.

As the Center for Photochemical Sciences marks its 40th anniversary, the Sivaguru-Tarnovsky partnership exemplifies the collaborative spirit that has defined CPS from its founding. The world's only PhD program in photochemical sciences has always been built on the premise that the most important questions in photochemistry sit at the boundaries between disciplines — and that answering them requires colleagues who trust each other enough to bring their best tools and their sharpest thinking to a shared problem. The 2025 publications show what that trust produces.

2025 Publications — Sivaguru & Tarnovsky Laboratories

Garg, D., Tarnovsky, A.N., & Sivaguru, J. (2025). Deciphering Photochemical Reactivity of Maleimides by Ultrafast Spectroscopy: How Minor Pathways Have Major Implications in Photochemical Reactions. Journal of Physical Chemistry A, 129(17), 3876–3885. https://doi.org/10.1021/acs.jpca.5c01860

Obloy, L.M., Valloli, L.K., Blanco Gonzalez, A., Garg, D., Bezabih, M.S., Olivucci, M., Tarnovsky, A.N., & Sivaguru, J. (2025, online; 2026 issue). Deciphering the Novel Photoreactivity of β-Enaminones. Angewandte Chemie International Edition. https://doi.org/10.1002/anie.202519037

For more about Dr. Sivaguru's research: bgsu.edu/arts-and-sciences/chemistry/faculty/jayaraman-sivaguru  ·  For Dr. Tarnovsky's research: tarnovskylab.wordpress.com

FACULTY RESEARCH SPOTLIGHT · 2025

Light as the Trigger: Engineering Materials That Release a Healing Gas on Command

Alexis D. Ostrowski, Ph.D.  ·  Professor  ·  Associate Dean  ·  Department of Chemistry & Center for Photochemical Sciences

Nitric oxide — a molecule so simple it contains just one atom of nitrogen and one of oxygen — is one of the most versatile chemical messengers in the human body. It widens blood vessels to regulate blood pressure. It helps neurons communicate. It activates the immune system to destroy invading bacteria and cancer cells. It accelerates wound healing. It prevents blood clots from forming on medical implants. And at higher concentrations, delivered directly to tumors, it can trigger cancer cell death.

The problem is delivery. Nitric oxide is a gas, and a reactive one. It exists in the body only transiently, lasting seconds before reacting with oxygen, hemoglobin, or other molecules. Introducing it therapeutically — getting the right amount, to the right tissue, at the right time — has proven extraordinarily difficult with conventional approaches. Too little, and there is no effect. Too much, and the same molecule that kills cancer cells can damage healthy tissue.

For more than a decade, Dr. Alexis Ostrowski, Professor and Associate Dean in BGSU's Department of Chemistry and Center for Photochemical Sciences, has been working on an elegant solution to this problem: materials that store nitric oxide in a chemically stable form and release it only when triggered by light. The concept — a photoresponsive nitric oxide-releasing material — holds the promise of on-demand delivery with spatial and temporal precision that no other method can match. Illuminate a wound, a tumor, or a medical device coating, and the material releases a precise, localized dose of nitric oxide exactly where it is needed.

The central challenge has been making these materials work with the kind of light that can actually penetrate human tissue. Blue and ultraviolet light, while effective at triggering photochemistry, are absorbed and scattered by skin and tissue within micrometers. Red and near-infrared (NIR) light, by contrast, penetrates centimeters into tissue — enough to reach tumors, blood vessels, and implanted devices. Building a nitric oxide-releasing material that responds efficiently to red and NIR light, rather than UV, is the key to making the technology clinically practical.

"Light gives us something no other trigger can: precision. We can decide exactly when and exactly where the nitric oxide is released — and tissue-penetrating red and NIR light means we can do it from outside the body."

A 2025 preprint published on ChemRxiv — a collaboration between the Ostrowski Lab and the Furgal Materials Workshop, also at BGSU — reports significant advances in this mission, using systematic chemical modifications of a ruthenium-salen scaffold to maximize NO release under red and NIR light, and demonstrating that a polymer architecture dramatically boosts performance.

Preprint on: ChemRxiv · 2025

Authors: F. Naser Aldine, D.A. Muizzi, I.F. Baraza, J.C. Furgal, A.D. Ostrowski

DOI: 10.26434/chemrxiv-2025-hgplj

THE RUTHENIUM-SALEN PLATFORM

The molecule at the heart of this research is a ruthenium-salen nitrosyl complex — a coordination compound in which a ruthenium metal center sits inside a tetradentate salen ligand (a symmetric, nitrogen- and oxygen-donating framework derived from salicylaldehyde and a diamine), with a nitric oxide molecule bound to the metal through a nitrogen atom. This NO ligand is held in a stable {RuNO}^6 configuration under ambient conditions — it does not spontaneously dissociate. But when the complex absorbs light, the energy disrupts the Ru–N bond, releasing NO as a free radical that can then exert its biological effects.

The salen ligand family is particularly attractive for this purpose because of its extraordinary tunability. By modifying the substituents on the salen aromatic rings or the diamine bridge, chemists can alter the electronic properties of the complex with precision — changing which wavelengths of light it absorbs, how efficiently it converts that light into chemistry (the quantum yield), and how the released NO interacts with its local environment. The salen framework is also thermally stable, synthetically accessible, and compatible with incorporation into polymer backbones and other material formats.

The benchmark compound — the well-known RuNO(Salen) complex — had already been shown in prior work from the Ostrowski Lab to release NO under red and NIR light, making it stand out from many photolabile NO donors that require UV irradiation. The 2025 work builds directly on that foundation, asking: how can systematic modification of the salen structure push the quantum yield higher, extend the NIR response, and ultimately make this platform suitable for practical biomedical applications?

WHAT THE STUDY FOUND

The research team synthesized the standard RuNO(Salen) complex as a reference point, characterizing its NO release under red (627 nm) and NIR (810 nm) light with quantum yields of 0.107 ± 0.01 and 0.00100 ± 0.00007, respectively. These values — the probability that an absorbed photon leads to NO release — established the baseline for systematic improvement.

A series of structurally modified salen ligands was then synthesized and incorporated into ruthenium nitrosyl complexes. The key variable was the substitution pattern on the salen aromatic rings — specifically, what functional groups were placed at different positions on the phenyl rings flanking the imine linkage. The team found that the position and identity of substituents had a pronounced effect on photoreactivity.

The standout finding was clear: introduction of a hydroxyl (–OH) group at the 4-position of the salen ring, in a geometry meta to the imine nitrogen, emerged as the ideal configuration for maximizing NO release under red and NIR light. This structural feature — a hydrogen bond donor positioned in a specific relationship to the metal-binding imine — appears to modulate the electronic structure of the complex in a way that promotes more efficient photodissociation of the NO ligand specifically at longer wavelengths. The result is a structurally simple modification with a disproportionately large effect on the photochemistry that matters most for biological applications.

A single –OH group in the right position on the salen ring: a small structural change with an outsized effect on the photochemistry that matters for tissue-penetrating light.

Even more striking was the second major finding: when the researchers incorporated the ruthenium complex into a polymer architecture — using a longer alkyl chain to covalently link the ruthenium-salen unit into a polymeric material — NO release was significantly enhanced relative to the small-molecule complex. The polymer architecture appears to create a local chemical environment around the ruthenium center that promotes more efficient interaction with nitrosated species following the initial photodissociation event. In practical terms, this means that the material format itself is a design variable — that embedding the photoactive ruthenium complex in a polymer matrix is not merely a delivery strategy, but a way to boost the fundamental photochemical performance of the system.

WHY IT MATTERS

The significance of this work operates on several levels, spanning fundamental photochemistry to biomedical engineering.

At the molecular level, the systematic structure-property relationships established here — the effect of salen substituent position and identity on quantum yield under red and NIR light — provide a rational design roadmap for the field. Prior work on ruthenium-salen NO donors had largely explored the benchmark complex without systematically mapping how structural variations affect performance at clinically relevant wavelengths. This paper fills that gap, identifying the –OH substitution at the 4-position as a specific, synthetically accessible handle for optimization.

At the materials level, the polymer enhancement finding is particularly consequential. The ability to incorporate ruthenium-salen NO donors into polymer backbones while simultaneously improving their photochemical performance opens the door to a wide range of material formats: coatings for medical implants that release NO to prevent biofilm formation and promote tissue integration; wound dressings that deliver NO phototherapeutically when illuminated; injectable polymer nanoparticles that accumulate in tumors and release NO upon external NIR illumination; and tunable hydrogels whose mechanical and chemical properties can be modulated by light through the same photochemistry that releases NO.

The collaboration with the Furgal Materials Workshop is essential to this vision. Professor Joseph Furgal's expertise in silsesquioxane-based hybrid materials and photoresponsive polymer systems complements the Ostrowski Lab's photochemical and coordination chemistry expertise to create materials that could not be designed by either group alone. The CPS 40th anniversary is an appropriate moment to highlight this kind of intra-center collaboration as a model for how BGSU's photochemical sciences program achieves impact beyond what any single laboratory could accomplish.

THE OSTROWSKI LAB: A DECADE OF LIGHT-CONTROLLED MATERIALS

The 2025 preprint is the latest chapter in a sustained research program that Dr. Ostrowski has developed at BGSU since joining the faculty in 2012. The program's defining idea — using metal ion coordination chemistry to create polymer materials whose properties respond to light in ways that purely organic polymers cannot — has been developed across more than a decade of NSF-funded research, including a 2017 NSF CAREER Award.

Nitric oxide release is one of several photoresponsive functions that the Ostrowski Lab has demonstrated in metal-containing polymer systems. Other work from the group has explored vanadium coordination chemistry to control the mechanical properties of polysaccharide hydrogels under light irradiation — creating materials that change stiffness and patterned spatial properties in response to illumination. The laboratory has also contributed to the development of copper-based luminescent sensors for real-time viscosity monitoring in industrial adhesives, and to early work on plasmonic nanocrystal solar cells in collaboration with the Zamkov group.

What unites these diverse projects is a consistent design philosophy: introduce a metal ion into a polymer or soft material framework, and the material gains photochemical capabilities — the ability to respond to specific wavelengths of light with specific chemical or physical changes — that are inaccessible to purely organic systems. The metal provides the photochemical "knob"; the ligand framework and polymer architecture define the response.

The 2025 work demonstrates this philosophy applied to one of its most medically consequential expressions: the light-controlled release of a potent biological signaling molecule, optimized for the wavelengths that can reach deep into living tissue. Dr. Irene Baraza, whose PhD was awarded in 2025 and who is a named co-author on the preprint, is among the graduate student contributors whose experimental work underpins these results — a testament to the Ostrowski Lab's ongoing investment in training the next generation of photoresponsive materials chemists.

RESEARCH IN CONTEXT

Light-Controlled Nitric Oxide: The Road from Photochemistry to the Clinic

The path from a novel photochemical finding to a clinical medical technology is long, and the 2025 preprint represents an important intermediate milestone rather than a finished product. The structure-property relationships and polymer enhancement demonstrated here are the kind of fundamental, reproducible results that provide the design knowledge needed to make the next generation of materials — ones optimized for specific clinical applications, tested for biocompatibility, and eventually incorporated into devices or formulations that can be evaluated in biological models.

That path is already underway in the Ostrowski Lab. The group's ongoing collaboration with the Furgal Materials Workshop is focused specifically on designing new photoresponsive silsesquioxane materials — hybrid organic-inorganic networks — that release NO after NIR light irradiation. The silsesquioxane platform, developed extensively in Furgal's laboratory, offers a robust and highly tunable polymer architecture that can incorporate metal complexes in defined structural environments — exactly the kind of control needed to translate the quantum yield improvements demonstrated in the 2025 work into practical materials.

Meanwhile, the broader context of the work is growing more urgent. Antibiotic-resistant biofilms on medical implants, chronic wounds that fail to heal, and the persistent need for safer, more targeted cancer treatments are all clinical challenges where nitric oxide's unique biology offers potential solutions that conventional drugs cannot easily provide. Light-controlled, materials-based NO delivery is increasingly recognized as a viable path to meeting those needs — and the systematic photochemical optimization achieved in the 2025 preprint puts the Ostrowski Lab's approach on firmer scientific footing than ever before.

As the Center for Photochemical Sciences marks its 40th anniversary, Dr. Ostrowski's research program stands as an example of the CPS's core mission made tangible: bringing the tools of photochemistry — light, molecules, and materials — to bear on problems that matter in the real world, and doing so with the kind of rigorous, fundamental science that makes the solutions last.

2025 Preprint — Ostrowski Laboratory

Naser Aldine, F., Muizzi, D.A., Baraza, I.F., Furgal, J.C., & Ostrowski, A.D. (2025). Tuning Quantum Yield to Maximize Nitric Oxide Release Under Red and NIR Light in Photoresponsive Ruthenium Salen Materials. ChemRxiv. https://doi.org/10.26434/chemrxiv-2025-hgplj

Note: This work was deposited as a preprint on ChemRxiv in 2025 and is currently undergoing peer review for publication in a peer-reviewed journal.

For more about Dr. Ostrowski's research, visit ostrowskilab.org  or  bgsu.edu/arts-and-sciences/chemistry/faculty/alexis-d-ostrowski

FACULTY RESEARCH SPOTLIGHT · 2025

Light, Life, and the Computer: Mapping How Biology Harnesses the Sun

Massimo Olivucci, Ph.D.  ·  Research Professor  ·  Director, Laboratory for Computational Photochemistry and Photobiology  ·  Department of Chemistry & Center for Photochemical Sciences

Every time you see, you are witnessing one of the fastest chemical reactions in biology. The moment light enters your eye, a molecule called retinal — tucked inside a protein called rhodopsin — absorbs a photon and flips its shape in less than one picosecond: one trillionth of a second. That molecular flip is the first event in vision, and it triggers a cascade that eventually becomes a nerve signal in your brain.

How does this happen so fast, so reliably, and with such precision? That question has driven the research career of Dr. Massimo Olivucci for more than three decades — first in Bologna and Siena, Italy, and since 2006 at BGSU's Center for Photochemical Sciences, where he directs the Laboratory for Computational Photochemistry and Photobiology.

Dr. Olivucci's approach is computational: he uses quantum mechanics and molecular dynamics simulations to construct extraordinarily detailed models of how light-absorbing proteins behave when they capture a photon. The models predict what happens at the electronic level — how the quantum mechanical wave functions of electrons rearrange, which chemical bonds break or rotate, and how the molecule finds its way from an excited electronic state back to the ground state through a feature of the energy landscape called a conical intersection.

But Dr. Olivucci's work has never been purely theoretical. His computational models are built to engage directly with experiment — to predict results that spectroscopists and biochemists can test, to explain observations that have resisted other explanations, and increasingly, to guide the engineering of entirely new light-responsive molecules and proteins for applications in medicine, renewable energy, and neuroscience.

"Computation is not a substitute for experiment — it is a partner. The goal is always a model that makes predictions you can actually test in the lab."

In 2025, Dr. Olivucci's group contributed to three published studies — each a different facet of the same overarching vision: using computation to understand, predict, and ultimately design the behavior of biological and biomimetic light-driven systems.

01  Engineering a Better Brain Probe

Published in: Chemical Science, 16(2), 761–774 · 2025

Authors: K. Herasymenko, D. Walisinghe, M. Konno, L. Barneschi, I. de Waele, M. Sliwa, K. Inoue, M. Olivucci, S. Haacke

DOI: 10.1039/D4SC05120C

Collaborating Institutions: University of Strasbourg, BGSU, University of Tokyo, University of Siena, University of Lille, Institut Polytechnique de Paris

THE CHALLENGE: SEEING VOLTAGE IN LIVING NEURONS

One of the most coveted tools in neuroscience is a genetically encoded voltage indicator — a protein that can be expressed inside neurons and that changes its fluorescence in real time as the electrical voltage across the cell membrane fluctuates. If you could watch voltage change in a living, behaving brain with single-neuron resolution, you could read out the activity of neural circuits directly, without implanting electrodes.

A family of proteins derived from archaeal light-driven proton pumps — collectively called Archaerhodopsins — has emerged as a promising platform for building such indicators. One member of this family, Archaerhodopsin-3 (AR-3), is particularly notable: its variants display a weak but voltage-sensitive near-infrared fluorescence that has already been demonstrated in cell cultures and small animals. But "weak" is the operative word. The fluorescence quantum yield of AR-3 is very low, which means most photons absorbed by the protein are not converted to emitted light — they are lost to photochemical reactions instead. To make a truly useful neuronal voltage sensor, researchers need to understand exactly why AR-3 fluoresces so little, and how to change that.

WHAT THE STUDY FOUND

This paper presents a combined experimental and computational investigation of AR-3 and two of its engineered variants — DETC and Arch-5 — that are known to display enhanced fluorescence. The goal was to characterize the ultrafast light-response of these proteins and understand, at the molecular level, why their fluorescence behavior differs from the wild-type.

The experimental side, led by the Haacke group in Strasbourg and the Inoue group in Tokyo, used transient spectroscopy to measure the excited-state dynamics of the proteins on ultrafast timescales. These experiments revealed that the fluorescent variants always display a mixture of two chromophore configurations — all-trans/15-anti and 13-cis/15-syn isomers — which leads to a bi-exponential decay pattern in their excited states.

The computational side, spearheaded by BGSU's Danushka Walisinghe and Dr. Olivucci in collaboration with the Siena group, built detailed QM/MM (quantum mechanics/molecular mechanics) models of the protein and its chromophore to explain the spectroscopic observations at the electronic level. A critical finding: the isomerization quantum yield in the fluorescent variants is reduced by more than 20-fold compared to wild-type AR-3. That dramatic reduction means the chromophore spends far less time undergoing its usual photochemical reaction — and instead emits the absorbed energy as fluorescence.

The study also confirmed that the steady-state fluorescence observed in these variants is induced by a single photon absorption event — an important mechanistic clarification that rules out more complex multi-photon processes and has direct implications for how these proteins can be used in imaging.

A 20-fold reduction in photoisomerization is the molecular signature of a protein that has been quietly repurposed — from a pump to a light bulb.

WHY IT MATTERS

This work provides the mechanistic foundation for rationally engineering the next generation of AR-3-based neuronal voltage sensors. By identifying precisely why the fluorescent variants behave differently — and validating those explanations with QM/MM models that can be applied to any AR-3 mutant — the study opens a direct path to computational screening of new variants before they are ever synthesized in the lab.

For neuroscience, the stakes are high. A sufficiently bright, voltage-sensitive fluorescent rhodopsin would enable the kind of all-optical neural recording that is currently only achievable with much more invasive methods. The Olivucci group's computational framework, which has already been applied to model dozens of rhodopsin variants through the ARM (Automatic Rhodopsin Modeling) platform, is directly positioned to accelerate that development.

02  A Protein and a Solar Cell, United by Computation

Published in: Journal of Chemical Theory and Computation, 21(6), 3231–3245 · 2025

Authors: M. Avelar, C. Coppola, A. D'Ettorre, A. Ienco, M.L. Parisi, R. Basosi, A. Santucci, M. Olivucci, A. Sinicropi

DOI: 10.1021/acs.jctc.4c01370

Collaborating Institutions: University of Siena, National Research Council of Italy (CNR)

THE VISION: A BIOHYBRID SOLAR DEVICE

Bacteriorhodopsin — the light-harvesting membrane protein found in salt-loving archaea — is one of nature's most elegant solar energy converters. When light strikes its retinal chromophore, the protein undergoes a precisely orchestrated photochemical cycle that pumps protons across a membrane, creating an electrochemical gradient that can be used to store energy. Unlike the complex photosystems of plants, bacteriorhodopsin does this with a single protein, a single chromophore, and a molecular precision that has fascinated chemists and engineers for decades.

One of the most intriguing applications being explored is the use of bacteriorhodopsin as a biological sensitizer for titanium dioxide (TiO2) — the same semiconductor that sits at the heart of conventional dye-sensitized solar cells. The idea: couple the protein's extraordinary photon-harvesting ability to TiO2's electron-conducting properties to create a biohybrid photovoltaic or photoelectrochemical device that is both efficient and based on renewable, biologically derived components.

But before that vision can be realized, researchers need to understand exactly how bacteriorhodopsin and TiO2 interact at the molecular level — how the protein attaches to the semiconductor surface, how the chromophore's photochemistry is affected by that attachment, and whether the photoinduced electron transfer processes that would power a device actually proceed as hoped.

WHAT THE STUDY ACCOMPLISHED

This paper presents the first detailed in silico (computational) study of a bacteriorhodopsin/TiO2 hybrid system at the molecular level. Using a combination of steered molecular dynamics (SMD-MD) and QM/MM simulations — the same computational toolkit that the Olivucci group has refined over decades for studying retinal proteins — the team modeled a gas-phase, isolated bR/TiO2 system and applied it to characterize the structural and electronic properties of the interface.

The simulations reveal how the protein positions itself relative to the TiO2 surface, which amino acid residues are involved in the interface, and how the retinal chromophore's electronic structure and photochemical reactivity are perturbed by proximity to the semiconductor. The QM/MM framework allows the electronic degrees of freedom of the chromophore to be treated quantum mechanically — capturing the subtleties of excited-state behavior that classical force fields cannot describe — while the protein and TiO2 environment are modeled at a less computationally expensive level.

The study provides what the field has lacked: a molecular-level baseline for understanding how the photochemical function of bacteriorhodopsin is modified when it is tethered to an inorganic semiconductor surface. This is essential information for anyone trying to design or optimize such biohybrid devices.

To build a biohybrid solar device, you first need to understand the conversation happening at the protein-semiconductor interface — atom by atom.

WHY IT MATTERS

The convergence of biological photochemistry and materials science for renewable energy is one of the most active frontiers in applied chemistry. Bacteriorhodopsin-based biophotovoltaics have been studied experimentally for years, but progress has been limited by an incomplete understanding of the molecular interactions at the protein-semiconductor junction. This computational study fills a fundamental gap, providing the mechanistic picture that can guide the rational design of more effective biohybrid architectures.

It also represents a natural extension of the Olivucci group's broader mission: using high-level computational photochemistry not just to explain phenomena, but to provide the molecular-level insight that makes engineering possible. From designing better neuronal probes to modeling biological solar converters, the approach is the same — understand the photochemistry first, at the quantum level, and the applications will follow.

03  A Molecular Switch with a Reset Button

Published in: Journal of Physical Chemistry B, 129(11), 2845–2855 · 2025

Authors: N. Ferrara, G. Giuliani, M. Maimaris, S. Prioli, M. Manathunga, L. Blancafort, M. Olivucci, M. Paolino

DOI: 10.1021/acs.jpcb.4c07003

Collaborating Institutions: University of Siena, University of Girona, BGSU

MOLECULAR SWITCHES AND THEIR LIMITATIONS

A molecular photoswitch is a molecule that can be toggled between two stable states by exposure to light — one state produced by irradiation with one wavelength, the other by irradiation with a different wavelength or by thermal relaxation in the dark. These switches are of intense interest for applications ranging from smart materials and drug delivery to data storage and bioimaging, because they offer a way to control chemical function with light: non-invasive, fast, and remotely applicable.

Most photoswitches operate as simple binary systems: light-on and light-off. But many real-world applications demand more — specifically, the ability to reset the switch to a defined initial state using a second, independent stimulus. If a photoswitch could be toggled by light and then reset by a chemical signal (like a change in pH), it would open the door to a new class of responsive materials that can be both optically controlled and chemically regenerated.

This paper addresses exactly that challenge, using a biomimetic approach: starting from the molecular architecture of GFP — the famous green fluorescent protein whose chromophore has become a model system for studying biological photochemistry — to design synthetic photoswitches that incorporate pH-sensitivity as a built-in reset mechanism.

WHAT THE STUDY ACHIEVED

The starting point is a biomimetic photoswitch (compound 1) whose core structure mimics the chromophore of the green fluorescent protein. This molecule can be toggled between two isomeric forms by light, making it a functional photoswitch. The team's innovation was to introduce a third control element — a "reset button" — by substituting the pyrrolidinone nitrogen atom with either a methane sulfonic (compound 2a) or toluene sulfonic (compound 2b) functional group.

The effect of this structural modification is precisely targeted: it alters the electronic distribution within the molecule in a way that makes the phenolic group — a pH-sensitive site — functionally important. When base (KOH) is added to deprotonate the phenolic moiety, the Z-isomer of the switch becomes thermally unstable and spontaneously converts to the E-form. Crucially, this process is reversible: adding acid (acetic acid) re-protonates the phenol, restoring the original relative stability of the two isomers and fully recovering the molecule's photochemical properties.

The combination of computational design (using the QM/MM methods developed in Olivucci's group, with BGSU's Madushanka Manathunga as a key contributor) and experimental synthesis and characterization (led by the Paolino and Giuliani groups in Siena) allowed the team to predict, make, and validate these compounds in a tightly integrated workflow.

A photoswitch with a reset button: light writes the state, and chemistry erases it — the molecular equivalent of a rewritable memory.

WHY IT MATTERS

This work establishes proof-of-concept for a new design principle: pH-resettable photoswitches built on the GFP chromophore scaffold. The ability to reset a photoswitch chemically — returning it to a well-defined initial state without additional light exposure — is a significant functional advance over conventional two-state switches, particularly for applications where precise control and reproducibility are essential.

The GFP scaffold is especially appealing because it is well-characterized, biologically compatible, and can be incorporated into larger molecular architectures. pH-sensitive switches based on this scaffold could find application in pH-responsive drug delivery systems, in sensors that detect local acidity (relevant to tumor microenvironments, for instance), or as functional elements in light-controlled smart materials that are also responsive to their chemical environment.

The computational-experimental integration showcased in this paper — where theory guides synthesis rather than merely following it — is a hallmark of the Olivucci group's approach and a model for how modern chemical research can be accelerated.

A UNIFIED RESEARCH VISION

Computation as a Bridge Between Biology, Physics, and Engineering

Three papers, three different systems, three different journals — but a single coherent scientific vision runs through all of them. Whether the subject is a neuronal voltage sensor derived from a microbial proton pump, a biohybrid solar device coupling a protein to a semiconductor, or a synthetic photoswitch inspired by a fluorescent jellyfish protein, the underlying questions are the same: how does light drive molecular change, what are the quantum mechanical pathways that make that change fast and selective, and how can we use that understanding to design molecules and materials with new capabilities?

Dr. Olivucci has pursued those questions across more than three decades and two continents, building what his colleagues describe as an unparalleled mechanistic understanding of rhodopsin photochemistry and its computational foundations. That understanding has generated tools — most notably the ARM (Automatic Rhodopsin Modeling) platform — that are now being used by research groups worldwide to model retinal proteins computationally, making computational photobiology a routine part of the protein engineering toolkit.

The 2025 publications reflect the natural expansion of this program: from characterizing known systems to engineering new ones, from explaining natural photochemistry to designing synthetic analogs, from single proteins to hybrid protein-material interfaces. Graduate and postdoctoral researchers at BGSU — including Danushka Walisinghe and Madushanka Manathunga — are central contributors to this expanding portfolio, carrying the computational photochemistry tradition forward as the field enters an era when biology and materials science are increasingly inseparable.

As the Center for Photochemical Sciences marks its 40th anniversary, Dr. Olivucci's laboratory stands as one of its most globally connected research nodes — with active collaborations spanning Strasbourg, Tokyo, Siena, Girona, and Lille — and one of its most forward-looking, building the computational foundations that will underpin the next generation of photochemical science.

2025 Publications — Olivucci Laboratory

Herasymenko, K., Walisinghe, D., Konno, M., Barneschi, L., de Waele, I., Sliwa, M., Inoue, K., Olivucci, M., & Haacke, S. (2025). Archaerhodopsin 3 is an ideal template for the engineering of highly fluorescent optogenetic reporters. Chemical Science, 16(2), 761–774. https://doi.org/10.1039/D4SC05120C

Avelar, M., Coppola, C., D'Ettorre, A., Ienco, A., Parisi, M.L., Basosi, R., Santucci, A., Olivucci, M., & Sinicropi, A. (2025). In Silico Study of a Bacteriorhodopsin/TiO2 Hybrid System at the Molecular Level. Journal of Chemical Theory and Computation, 21(6), 3231–3245. https://doi.org/10.1021/acs.jctc.4c01370

Ferrara, N., Giuliani, G., Maimaris, M., Prioli, S., Manathunga, M., Blancafort, L., Olivucci, M., & Paolino, M. (2025). Design, Synthesis, and Characterization of pH-Resettable Photoswitches Mimicking the GFP Fluorophore Structure. Journal of Physical Chemistry B, 129(11), 2845–2855. https://doi.org/10.1021/acs.jpcb.4c07003

Olivucci, M. (2025). A Scientific Autobiography. Journal of Physical Chemistry B, 129(32), 8077–8086. https://doi.org/10.1021/acs.jpcb.5c04288  [Festschrift issue dedicated to Massimo Olivucci — invited autobiography]

For more about Dr. Olivucci's research, visit lcpp.bgsu.edu  or  bgsu.edu/arts-and-sciences/center-for-photochemical-sciences/ResearchFaculty/massimo-olivucci

FACULTY RESEARCH SPOTLIGHT · 2025

Feeling the Pressure: How Mechanical Forces Shape Life at the Molecular Scale

H. Peter Lu, Ph.D.  ·  Ohio Eminent Scholar and Professor  ·  Department of Chemistry & Center for Photochemical Sciences

Most of what we know about proteins and cell membranes comes from studying them at rest — or under tension, the way a rubber band stretches. But biology is rarely that tidy. Cells jostle, squeeze, and press against each other constantly, and the molecular machinery inside responds in ways that researchers are only beginning to understand.

In 2025, the laboratory of Dr. H. Peter Lu — Ohio Eminent Scholar and Professor in BGSU's Department of Chemistry and Center for Photochemical Sciences — published four peer-reviewed studies that push this frontier forward. Together, they reveal a new dimension of how proteins and cell membranes behave under mechanical compression, and what that means for cell signaling, drug action, and the physics of life itself.

"What we are discovering is that compression is not just a passive force — it is a language that cells and proteins use to communicate and change their behavior."

Using custom-modified atomic force microscopy (AFM), patch-clamp electrophysiology, confocal fluorescence imaging, and molecular dynamics simulation, Dr. Lu's team is building a toolkit for probing biology's softest machinery at the hardest-to-reach scales — piconewtons of force, nanometers of structure, microseconds of time.

01  A Cancer-Linked Receptor That Breaks Under Pressure

Published in: Journal of Physical Chemistry B, 129(22), 5411–5422 · May 2025

Authors: Dedunu S. Senarathne, Lalita Shahu, H. Peter Lu

DOI: 10.1021/acs.jpcb.5c00800

The epidermal growth factor receptor — better known by its acronym EGFR — is one of the most studied proteins in cancer biology. It sits on the surface of cells, receives chemical signals from the environment, and tells the cell whether to grow, divide, or die. Mutations in EGFR drive some of the most aggressive forms of lung, breast, and colorectal cancer.

Yet for all that attention, researchers had never observed what happens to EGFR when a cell is physically compressed — a routine mechanical event in living tissue, especially in tumors, which are often stiffer and under more pressure than healthy cells.

Dr. Lu's lab changed that. Using a home-modified AFM with an ultrasoft tip capable of exerting forces measured in piconewtons — roughly one trillionth of a Newton, or the force a single bacterium might exert — the team probed both unliganded EGFR monomers (without their chemical signal) and EGF-bound EGFR monomers and dimers (with it).

What they found was unexpected: under piconewton-level compressive forces in the range of tens to hundreds of piconewtons, both forms of EGFR can undergo spontaneous tertiary structural rupture — a sudden, catastrophic unfolding of the protein's three-dimensional architecture. This behavior had never been observed before.

A previously hidden behavior that may play a significant role in protein cell signaling.

The finding matters because it suggests that the physical microenvironment of a cell — how stiff or soft the tissue is, how tightly cells are packed together — may directly influence EGFR signaling in ways that have nothing to do with chemistry. In tumor biology, where mechanical stiffness is a known feature of malignant tissue, this could open new lines of inquiry into how cancer cells evade normal signaling constraints.

02  Inside the Rupture: Water, Voids, and the Physics of Protein Failure

Published in: Journal of Physical Chemistry B, 129(40), 10272–10284 · 2025

Authors: Dedunu S. Senarathne, Lalita Shahu, H. Peter Lu

DOI: 10.1021/acs.jpcb.5c04689

Discovering that proteins rupture under compression is one thing. Understanding why is another — and that is the question Dr. Lu's second 2025 paper takes on.

Every protein contains void volumes: pockets of empty space within its folded structure. These voids are not defects — they are intrinsic features of how proteins pack their amino acid chains together, and they influence a protein's compressibility, flexibility, and resilience. Similarly, the water molecules that surround a protein — its hydration shell — play a dynamic role in stabilizing its structure.

In this study, the team combined their experimental AFM compression data with analysis of void volumes and hydration dynamics to build a mechanistic picture of how proteins fail under external force. They found that the way a protein's internal architecture responds to compression — specifically, how void spaces collapse and how the hydration shell shifts — determines both the threshold at which rupture occurs and the nature of the structural collapse.

In essence, a protein's empty spaces and surrounding water are not passive bystanders. They are active participants in the physics of mechanical failure.

This work provides a theoretical and experimental foundation for understanding a broad class of force-induced protein behaviors, with implications for mechanobiology, protein engineering, and diseases linked to abnormal protein mechanics — including neurodegeneration and cardiovascular disease.

03  Force as a Switch: Activating an Enzyme Without Calcium

Published in: ACS Omega, 10(35), 39823–39832 · 2025

Authors: Lalita Shahu, Yadav Prasad Gyawali, Ting Jiang, Dedunu S. Senarathne, Changjian Feng, H. Peter Lu

DOI: 10.1021/acsomega.5c03891

Nitric oxide is one of the body's most versatile signaling molecules. Produced in neurons, blood vessels, and immune cells, it regulates blood pressure, modulates neurotransmitter release, and helps coordinate the immune response. The enzyme responsible for producing nitric oxide in neural tissue — neuronal nitric oxide synthase, or nNOS — is therefore a molecule of significant biomedical interest.

The canonical model of nNOS activation holds that calcium-bound calmodulin (CaM), a calcium-sensing protein, must bind to nNOS to activate nitric oxide production. Without calcium, the thinking went, calmodulin cannot do its job. This model has guided nNOS research for decades.

Dr. Lu's team challenged it. Using a sophisticated combination of AFM and correlated confocal fluorescence microscopy, they directly probed nNOS activity while applying controlled mechanical compression to the system. The critical variable: calmodulin in its apo form — without calcium bound.

The result was a first: apo-calmodulin, manipulated by compressive mechanical force, was able to activate nNOS and trigger nitric oxide production — without calcium. The study demonstrated that mechanical force can function as a substitute activation signal, acting through apo-CaM as a mechanosensing protein.

Force itself can flip the switch — no calcium required.

The implications are substantial. Physical forces in neural tissue — from the constant movement of neurons, cerebrospinal fluid pressure, or traumatic impact — may be activating nNOS through this calcium-independent pathway without anyone noticing. This could be relevant to understanding traumatic brain injury, where mechanical forces and abnormal nitric oxide levels both play documented roles, as well as broader questions about mechanically regulated enzyme activity in the nervous system.

04  Methamphetamine at the Membrane: A New View of Drug-Induced Disruption

Published in: ACS Chemical Neuroscience, 16(12), 2260–2276 · 2025

Authors: Hashini R. Eheliyagoda, H. Peter Lu

DOI: 10.1021/acschemneuro.5c00088

The fourth study of 2025 takes a different approach to a different problem — one with direct relevance to the national opioid and stimulant drug crisis. Graduate student Hashini R. Eheliyagoda, working in Dr. Lu's lab, set out to characterize what methamphetamine actually does to a neuron's outer membrane at the molecular level.

The neuronal cell membrane is not a passive barrier. It is a dynamic, fluid bilayer of lipids that controls what enters and exits the cell, maintains the electrical gradients that enable neural signaling, and must recover rapidly from perturbation. It has long been known that methamphetamine disrupts this membrane — but the physical details of that disruption, and how the membrane tries to recover, had not been directly measured.

Eheliyagoda and Dr. Lu used whole-cell patch-clamp electrophysiology — the gold standard technique for measuring electrical currents across cell membranes — combined with differential interference contrast microscopy to probe live HT22 neuronal cells in the presence of methamphetamine. Their measurements revealed a concentration-dependent increase in membrane fluidity and permeability, producing what the researchers describe as "electric leaking states" — measurable increases in membrane conductance that reflect structural disruption.

To understand the mechanism at the molecular level, the team also ran molecular dynamics simulations. These computational studies revealed that methamphetamine molecules readily penetrate the lipid bilayer, clustering near the lipid headgroup layer — physically wedging themselves into the membrane architecture. The simulations provided quantitative free energy analysis of how deeply and how easily the drug permeates the membrane.

Critically, the team was also able to characterize the membrane's recovery dynamics — how quickly and completely the bilayer returns to its baseline state after perturbation. By analyzing the autocorrelation of electric current fluctuations in leaking versus nonleaking states, they could quantify the randomness and conformational dynamics of the disruption and recovery process.

The membrane does not simply "break" — it undergoes dynamic structural fluctuations, and the signature of that disruption can be read electrically.

This work establishes a new framework for understanding how stimulant drugs physically alter the neural membrane — not just through receptor interactions, but through direct mechanical disruption of the lipid bilayer. It also offers a method that could be applied to study other drugs, toxins, or disease states that compromise membrane integrity.

A UNIFIED RESEARCH VISION

The Mechanics of Molecular Life

These four papers, taken together, tell a coherent and compelling story. Dr. Lu's lab has established a distinct research identity at the intersection of biophysics, cell biology, and chemical spectroscopy — one defined by the conviction that mechanical forces are not background noise in biology, but active and underappreciated signals.

From a cancer receptor that ruptures under piconewton pressure, to a signaling enzyme that fires without its conventional trigger, to a critical protein's internal architecture governing its mechanical fate, to a street drug that physically embeds itself in a neuron's outer membrane — the common thread is the same: biology at the nanoscale responds to force in ways that matter, and that can now be measured.

The instrumentation that makes this possible — custom-modified AFM setups, AFM-correlated confocal microscopy, whole-cell patch-clamp combined with imaging, and high-resolution molecular dynamics simulation — represents years of methodological development in Dr. Lu's laboratory. Graduate students Dedunu Senarathne, Lalita Shahu, Yadav Prasad Gyawali, Ting Jiang, and Hashini Eheliyagoda contributed centrally to this body of work, reflecting the lab's ongoing investment in training the next generation of biophysical chemists.

As BGSU's Center for Photochemical Sciences marks its 40th anniversary, the Lu Laboratory's 2025 output exemplifies the kind of boundary-crossing, technique-driven science that has kept the CPS at the forefront of physical chemistry research for four decades.

2025 Publications — H. Peter Lu Laboratory

Senarathne, D.S., Shahu, L., & Lu, H.P. (2025). Probing the Epidermal Growth Factor Receptor under Piconewton Mechanical Compressive Force Manipulations. Journal of Physical Chemistry B, 129(22), 5411–5422. https://doi.org/10.1021/acs.jpcb.5c00800

Senarathne, D.S., Shahu, L., & Lu, H.P. (2025). Insights from Void Volumes and Hydration Dynamics on Protein Spontaneous Rupture via Dynamic Internal Impact Forces. Journal of Physical Chemistry B, 129(40), 10272–10284. https://doi.org/10.1021/acs.jpcb.5c04689

Shahu, L., Gyawali, Y.P., Jiang, T., Senarathne, D.S., Feng, C., & Lu, H.P. (2025). Compressive Force Activation of the Neuronal Nitric Oxide Synthase Enzyme. ACS Omega, 10(35), 39823–39832. https://doi.org/10.1021/acsomega.5c03891

Eheliyagoda, H.R. & Lu, H.P. (2025). Electric Patch-Clamp Probing and Computational Studies of Lipid Bilayer Structural Fluctuations Induced by Methylamphetamine on a Neuronal Cell Membrane. ACS Chemical Neuroscience, 16(12), 2260–2276. https://doi.org/10.1021/acschemneuro.5c00088

For more information about Dr. Lu's research, visit bgsu.edu/arts-and-sciences/chemistry/faculty/peter-lu