FACULTY RESEARCH SPOTLIGHT · 2023

Chemistry at the Frontier: Anzenbacher Group Expands Anion Sensing, PFAS Chemistry, and Quantum Shell Science

Pavel Anzenbacher, Jr., Ph.D.  ·  Director, Center for Photochemical Sciences  ·  Professor of Chemistry

In 2023, the Anzenbacher Group published three papers that span the full breadth of the group's research identity — a new receptor-sensor platform for anions, a perspective on emerging PFAS remediation chemistry, and a landmark JACS paper on nanocrystal engineering co-authored with multiple BGSU and international collaborators. Together they illustrate a research program that has always moved between fundamentals and applications, between molecular design and materials science, and between the laboratory and the real world.

Three papers in three different journals — each one a different facet of the same enduring question: how do we design molecules that recognize, detect, and bind the things we care about?

01  A New Platform for Anion Sensing in Water

Published in: Chemical Science, 14, 7545–7552 · 2023

Authors: A.R. Sartori, A. Radujević, S.M. George, P. Anzenbacher Jr.

DOI: 10.1039/D3SC01970E

BACKGROUND

Synthetic anion receptors fall into two broad families. Calix[4]pyrroles (CPs) provide directional N–H hydrogen bonds that grant selectivity but are limited in aqueous environments. Polyammonium azacrowns (ACs) offer strong, electrostatically driven binding but without selectivity. Combining the two in a single, covalently linked isosteric molecule had not been accomplished with rigorous binding characterization.

WHAT THE PAPER ACHIEVES

This Chemical Science paper introduces the calixpyrrole-azacrown (CP-AC) isostere — a hybrid receptor that is structurally and sterically analogous to both parent frameworks while integrating their complementary binding modes. By appending an environmentally sensitive dansyl fluorophore, the compound becomes both a receptor and a fluorescence sensor in a single molecule. Binding of anions — evaluated by NMR titrations and fluorescence measurements — showed the expected enhancement in both affinity and selectivity compared to either parent framework alone. The paper establishes the CP-AC isostere as a versatile new scaffold for anion recognition, directly setting the stage for the more elaborate hybrid receptors developed in the 2024 Chemistry–European Journal paper and the ongoing program in aqueous anion sensing.

Graduate students Austin Sartori, Aco Radujević, and Sandra George, whose names appear across the Anzenbacher group's 2023 and 2024 publications, contributed the core synthetic and spectroscopic work that established this platform.

Half calixpyrrole, half azacrown — isosteric, functional, and ready for the aqueous sensing challenges that matter most.

02  PFAS: A New Frontier for Metal-Organic Cage Chemistry

Published in: Trends in Chemistry, 6, 407–409 · 2023

Authors: A.R. Sartori, P. Anzenbacher Jr.

DOI: 10.1016/j.trechm.2023.04.005

Per- and polyfluoroalkyl substances — PFAS, widely known as 'forever chemicals' — are a growing environmental and public health crisis. These synthetic compounds, used in everything from nonstick cookware to firefighting foam, persist indefinitely in the environment and accumulate in biological tissues, with mounting evidence linking them to cancer, endocrine disruption, and developmental disorders. Removing them from water and soil is one of the most pressing challenges in environmental chemistry.

This Trends in Chemistry perspective, co-authored by Austin Sartori and Dr. Anzenbacher, evaluates an emerging approach to PFAS remediation: the use of metallacages — self-assembled metal-organic structures with well-defined interior cavities — as sensors and adsorbents for PFAS molecules. Metallacages can be designed with charged, fluorophilic, or size-complementary interiors that bind PFAS with high affinity, offering both detection and sequestration in a single functional architecture.

The perspective surveys the current landscape of PFAS sensing and remediation, assesses the promise and limitations of metallacage-based approaches relative to activated carbon, reverse osmosis, and other existing technologies, and identifies the key design challenges that must be solved for cage-based PFAS chemistry to become practically relevant. Published in Trends in Chemistry — a Cell Press journal dedicated to forward-looking perspectives — it signals the Anzenbacher group's engagement with one of applied supramolecular chemistry's most timely problems.

03  Quantum Shell in a Shell: Cross-Group Collaboration Produces a JACS Landmark

Published in: Journal of the American Chemical Society, 145, 13326–13334 · 2023

Authors: D. Harankahage, J. Cassidy, J. Beavon, J. Huang, N. Brown, D.B. Berkinsky, A. Marder, B. Kayira, M. Montemurri, P. Anzenbacher Jr., R.D. Schaller, L. Sun, M.G. Bawendi, A.V. Malko, B.T. Diroll, M. Zamkov

DOI: 10.1021/jacs.3c03397

Collaborating Institutions: BGSU (Zamkov, Anzenbacher, Sun Labs), MIT (Bawendi), UT Dallas (Malko), Argonne National Lab (Schaller, Diroll)

This landmark JACS paper — which appears on both the Anzenbacher and Zamkov publication lists — is described fully in the Zamkov Lab spotlight. The paper introduces the CdS-CdSe-CdS-ZnS quantum shell-in-a-shell architecture, which dramatically suppresses surface-related carrier losses by adding a final ZnS shell to the quantum shell structure. The result is nanocrystals capable of functioning at the high excitation intensities required for X-ray scintillation, multi-exciton LEDs, and laser gain media — capabilities that conventional quantum shells could not sustain without the additional surface passivation. Dr. Anzenbacher and Dr. Liangfeng Sun contributed spectroscopic characterization expertise, while Nobel co-laureate Moungi Bawendi's group at MIT provided critical materials and characterization support. The paper was selected for cross-disciplinary recognition in Nature Nanotechnology, where Dr. Zamkov authored an accompanying News & Views piece.

A UNIFIED RESEARCH VISION

The Anzenbacher Program in 2023: Breadth as a Strength

From a new isosteric receptor platform to a PFAS perspective to a co-authored JACS paper with Nobel-laureate collaborators, the Anzenbacher Group's 2023 output reflects a program that has always been willing to engage with questions beyond its immediate specialty. The CP-AC isostere paper is the Anzenbacher group at its core: precise molecular design, careful spectroscopic characterization, and a clear path from fundamental receptor chemistry to real sensing applications. The PFAS perspective is the group at its most forward-looking: scanning the horizon for problems where supramolecular chemistry can make a difference. And the JACS paper is the group at its most collaborative: bringing spectroscopic and materials science expertise to an interdisciplinary nanocrystal project where that expertise was essential.

Graduate students Austin Sartori, Aco Radujević, and Sandra George — whose names appear in the two Anzenbacher-led papers — are at the core of this output. Their contributions span synthesis, NMR characterization, fluorescence spectroscopy, and data analysis, and represent the kind of multifaceted graduate training that has been a hallmark of the Anzenbacher group for two decades.

2023 Publications — Anzenbacher Laboratory

Sartori, A.R., Radujević, A., George, S.M., & Anzenbacher, P., Jr. (2023). Azacrown-Calixpyrrole Isostere: Receptor and Sensor for Anions. Chemical Science, 14, 7545–7552. https://doi.org/10.1039/D3SC01970E

Sartori, A.R., & Anzenbacher, P., Jr. (2023). Metallacage-based Sensors and Absorbents for Polyfluoroalkyl Substances (PFAS). Trends in Chemistry, 6, 407–409. https://doi.org/10.1016/j.trechm.2023.04.005

Harankahage, D., Cassidy, J., Beavon, J., Huang, J., Brown, N., Berkinsky, D.B., Marder, A., Kayira, B., Montemurri, M., Anzenbacher, P., Jr., Schaller, R.D., Sun, L., Bawendi, M.G., Malko, A.V., Diroll, B.T., & Zamkov, M. (2023). Quantum Shell in a Shell: Engineering Colloidal Nanocrystals for a High-Intensity Excitation Regime. Journal of the American Chemical Society, 145, 13326–13334. https://doi.org/10.1021/jacs.3c03397

FACULTY RESEARCH SPOTLIGHT · 2023

Rethinking the Funnel: Olivucci and Boeije Rewrite the Theory of Ultrafast Photochemistry

Massimo Olivucci, Ph.D.  ·  Research Professor  ·  Director, Laboratory for Computational Photochemistry and Photobiology  ·  CPS

The story of how excited molecules return to their ground state has been told, for decades, through the language of conical intersections — the points on molecular energy landscapes where two electronic states become degenerate, creating a funnel through which excited molecules rapidly decay. The concept revolutionized photochemistry when it emerged in the 1990s, largely through the computational work of Massimo Olivucci and his collaborators. Conical intersections replaced the old notion that excited molecules decay slowly through radiative processes, explaining instead how photochemical reactions can happen in femtoseconds — trillionths of a second.

But the original theoretical framework for conical intersections was built around a simple, two-dimensional picture: two coordinates define the branching space at the intersection point, and the intersection itself is characterized by a double cone — the mathematical feature that gives conical intersections their name. This picture has been enormously productive, but it is also, by construction, incomplete. Real organic molecules have dozens or hundreds of nuclear degrees of freedom, and the conical intersection is not an isolated point but part of a seam — a high-dimensional manifold. The behavior of a molecule as it approaches and traverses this seam depends on all those coordinates, not just two.

A 2023 review in Chemical Society Reviews — co-authored by Olivucci with Yorrick Boeije of the University of Amsterdam, one of the most comprehensive treatments of conical intersection photochemistry published in years — argues that the time has come to move beyond the two-mode picture and develop a genuinely multi-mode understanding of how conical intersections govern ultrafast organic photochemistry.

Published in: Chemical Society Reviews, 52(8), 2643–2687 · March 2023

Authors: Y. Boeije, M. Olivucci

DOI: 10.1039/D2CS00719C

Affiliation of co-author: University of Amsterdam (Van 't Hoff Institute for Molecular Sciences)

THE ONE-MODE PICTURE AND ITS LIMITS

The classic description of a conical intersection involves two special nuclear coordinates — the gradient difference vector and the derivative coupling vector — that together define the branching plane, within which the two potential energy surfaces split apart from their point of degeneracy. Motion within this branching plane determines whether the molecule undergoes chemistry or returns to its starting configuration after passing through the intersection. Motions orthogonal to the branching plane — the "intersection space" — leave the energy degeneracy unchanged and are, in the classic picture, passive.

This framework has produced remarkable predictive power for simple systems — explaining why molecules like retinal and azobenzene isomerize so rapidly and with such high quantum efficiency, why excited aromatic molecules relax so fast, and how conical intersection topology controls the products of photochemical reactions. But it treats the intersection essentially as a point — characterized by a handful of properties evaluated at a single geometry — and the reaction dynamics as governed primarily by a single reaction coordinate and its interaction with the branching space.

Real photochemical dynamics are more complex. Multiple vibrational modes can be simultaneously relevant. The molecule may not reach the minimum energy conical intersection point at all, traversing the seam at some nearby geometry. The branching between product channels may be governed by dynamics far from the intersection. And coherent nuclear motion — wave-packet dynamics — can produce behavior that is fundamentally non-classical and cannot be captured by trajectory-based methods that treat the intersection as a fixed point.

THE MULTI-MODE FRAMEWORK

The 45-page review addresses these limitations systematically, surveying a wide range of organic photochemical reactions — including retinal isomerization, azobenzene photochemistry, electrocyclic reactions, and photofragmentation processes — through the lens of multi-mode conical intersection dynamics. The central argument is that understanding these reactions requires characterizing not just the minimum energy conical intersection and its local branching space, but the full topography of the intersection seam, the modes that couple to the seam, the role of tuning versus coupling modes in mediating the dynamics, and the interplay between coherent and incoherent nuclear motion.

For some systems, the multi-mode picture reveals new mechanisms that the one-mode view misses entirely. For example, in retinal photoisomerization — the reaction that underlies vision — the role of specific vibrational modes in synchronizing with the torsional reaction coordinate is essential to understanding why rhodopsin achieves 67% quantum efficiency while synthetic analogs fall short. This is precisely the finding that the 2024 Nature Communications paper (also from the Olivucci group) would go on to demonstrate computationally — and the 2023 review provides the theoretical framework that contextualizes it.

The review also surveys the computational methods available for studying multi-mode conical intersection dynamics, from the full multiconfigurational quantum mechanics approaches that have been the hallmark of the Olivucci group's work, to the trajectory-based and variational methods that can handle larger systems, to the machine learning approaches that are beginning to make high-dimensional potential energy surface exploration tractable. It is, in effect, a roadmap for the field — one that defines both what has been accomplished and what remains to be done.

The intersection is not a point — it is a seam. The seam is not two-dimensional — it is high-dimensional. And understanding how molecules traverse it requires a fundamentally new way of thinking about photochemical dynamics.

WHY IT MATTERS

A 45-page review in Chemical Society Reviews — one of chemistry's most prestigious venues for authoritative syntheses of research fields — is a significant investment of scholarship, and its reception reflects that. The paper has rapidly accumulated citations from across computational photochemistry, spectroscopy, and molecular physics, establishing it as a key reference for anyone working on ultrafast photochemical dynamics.

For the Olivucci group specifically, the review serves as both a synthesis of decades of work on conical intersections and a theoretical foundation for the next generation of research — work that increasingly focuses on multi-mode, multi-state dynamics in complex systems, from rhodopsins to molecular motors to photoswitches. The collaboration with Boeije, a specialist in the photochemistry of organic molecules and photoswitches, brings perspectives from the experimental spectroscopy community that complement the Olivucci group's primarily computational approach.

As the CPS marks its 40th anniversary, this review stands as one of the most intellectually ambitious papers produced by its faculty in 2023 — a statement not just about what the Olivucci group has done, but about where the entire field of computational photochemistry is going.

RESEARCH IN CONTEXT

From Theory to Application: The Olivucci Program in 2023

The 2023 Chemical Society Reviews paper sits in a precise relationship to the rest of the Olivucci group's research program. The 2022 Nature Communications paper demonstrated the two-stroke photon-only molecular motor. The 2024 Nature Communications paper would demonstrate the role of vibrational synchronization in rhodopsin's quantum efficiency. The 2023 review provides the theoretical architecture that connects these results — explaining why certain vibrational modes matter, why the multi-dimensional character of the conical intersection seam is relevant, and why the comparison between natural and synthetic molecular rotors reveals something fundamental about what makes photochemical machines efficient.

BGSU PhD researcher and co-author Yorrick Boeije — now at the University of Amsterdam — represents the kind of international research connection that the Olivucci group cultivates through its dual affiliation with BGSU and the University of Siena. Postdoctoral and graduate training in the Olivucci laboratory produces researchers who carry the computational photochemistry tradition to institutions worldwide, multiplying the group's scientific impact far beyond its immediate output.

2023 Publication — Olivucci Laboratory

Boeije, Y., & Olivucci, M. (2023). From a One-Mode to a Multi-Mode Understanding of Conical Intersection Mediated Ultrafast Organic Photochemical Reactions. Chemical Society Reviews, 52(8), 2643–2687. https://doi.org/10.1039/D2CS00719C

FACULTY RESEARCH SPOTLIGHT · 2023

The Shell of a Shell: Zamkov Lab Pushes Quantum Nanocrystal Science to New Heights

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

2023 was a year of consolidation and expansion for the Zamkov Lab's quantum shell program — consolidation in the sense that the group's foundational research on quantum shells received its most definitive expression in the form of three publications spanning JACS, Chemical Communications, and Nature Nanotechnology; expansion in the sense that those publications collectively established quantum shells as a mature platform, not merely a promising concept.

The year also brought an extraordinary piece of external validation: MIT's Moungi Bawendi, a co-author on the 2023 JACS paper from the Zamkov Lab, was awarded the Nobel Prize in Chemistry — one of three Nobel laureates recognized for the discovery and synthesis of quantum dots. For the Zamkov Lab, whose entire research program is dedicated to transcending the limitations of the quantum dot architecture, the recognition underscored both the scientific importance of the field and the timeliness of the quantum shell innovation.

The year the Nobel went to quantum dots was also the year the Zamkov Lab published its most important case for why what comes after quantum dots matters.

01  Quantum Shell in a Shell: Solving the Surface Problem

Published in: Journal of the American Chemical Society, 145, 13326–13334 · June 2023

Authors: D. Harankahage, J. Cassidy, J. Beavon, J. Huang, N. Brown, D.B. Berkinsky, A. Marder, B. Kayira, M. Montemurri, P. Anzenbacher Jr., R.D. Schaller, L. Sun, M.G. Bawendi, A.V. Malko, B.T. Diroll, M. Zamkov

DOI: 10.1021/jacs.3c03397

Collaborating Institutions: MIT (Bawendi), UT Dallas (Malko), Argonne National Lab (Schaller, Diroll), BGSU (Zamkov, Anzenbacher, Sun)

THE PROBLEM: SURFACE-RELATED CARRIER LOSSES

Quantum shells — semiconductor nanocrystals in which charge carriers are confined to a thin shell rather than a solid core — had already demonstrated their most important property by 2023: the suppression of Auger recombination, the non-radiative process that robs quantum dots of their efficiency under high excitation. But the quantum shell architecture introduced a new challenge: the shell geometry maximizes the surface-to-volume ratio, meaning charge carriers spend more time near surface defects that can trap them and produce non-radiative losses. Initial quantum shell designs suffered from this surface problem — Auger recombination was suppressed, but surface trapping kept overall efficiency below what the architecture's potential suggested.

THE SOLUTION: AN OUTER ZNS SHELL

This JACS paper introduces the quantum shell-in-a-shell architecture: a CdS core (bulk-like, large) surrounded by a thin CdSe emitting shell, which is in turn coated with a CdS barrier shell, and finally passivated by a ZnS outer shell. The four-layer structure — CdS/CdSe/CdS/ZnS — addresses surface carrier losses by burying the CdSe shell deep enough from the particle surface that carriers cannot reach surface trap states efficiently. The result is a dramatic improvement in overall quantum efficiency, enabling the quantum shells to perform at the high excitation intensities needed for X-ray scintillation, multi-exciton LEDs, and gain media.

The paper reports detailed characterization of the optical properties of these quantum-shell-in-a-shell structures, including transient absorption spectroscopy contributed by Richard Schaller and Benjamin Diroll at Argonne National Laboratory, photon correlation measurements contributed by Anton Malko's group at UT Dallas, and spectroscopic support from Dr. Anzenbacher and Dr. Sun at BGSU. The breadth of characterization — and the range of institutions represented — reflects the extent to which the Zamkov Lab's quantum shell program had by 2023 become a focus of collaborative attention across the photonic materials community.

Moungi Bawendi's group at MIT contributed expertise in nanocrystal synthesis and characterization that helped establish the structural basis for the shell-in-a-shell architecture. The Nobel committee's recognition of Bawendi, announced later in 2023, gave this collaboration an additional significance: the quantum shell work published in this paper directly advances the agenda of addressing the limitations that the Nobel-recognized quantum dot technology cannot overcome.

Surface trapping was the last major obstacle. The shell-in-a-shell architecture removes it — and opens the door to quantum shells in every high-intensity application.

02  Quantum Shells vs. Quantum Dots: The Definitive Case

Published in: Chemical Communications, 59, 11337–11348 · September 2023

Authors: J. Beavon, J. Huang, D. Harankahage, M. Montemurri, J. Cassidy, M. Zamkov

DOI: 10.1039/D3CC02091F

This Chemical Communications feature article — primarily authored by Zamkov Lab graduate students — provides the most comprehensive account of the quantum shell platform's advantages over conventional quantum dots that had appeared in a single place. The paper surveys the physics of Auger recombination and its consequences for device performance, explains the quantum shell geometry and the physical principles behind its Auger suppression, and systematically reviews the optical gain, lasing, LED, and scintillator applications that quantum shells enable but quantum dots cannot sustain.

The paper also reviews the synthesis of quantum shells — the colloidal chemistry required to grow a thin, uniform CdSe shell over a large CdS core with the right thickness and uniformity to produce optimal quantum confinement — and the characterization methods needed to confirm the shell structure and properties. It is, in effect, the Zamkov Lab's definitive account of the quantum shell concept: what it is, why it works, what it enables, and what comes next. Graduate students Jacob Beavon and Jiamin Huang, whose names appear as lead authors, made central contributions to the synthesis and characterization work underlying this review.

03  Nature Nanotechnology: The Nobel Year and What Comes After

Published in: Nature Nanotechnology, 18, 1365–1366 · 2023

Author: M. Zamkov

DOI: 10.1038/s41565-023-01493-1

The year 2023 saw the Nobel Prize in Chemistry awarded to Moungi Bawendi (MIT), Louis Brus (Columbia), and Aleksei Ekimov for the discovery and synthesis of quantum dots — nanocrystals whose optical properties are determined by quantum confinement at the nanoscale. The Nobel committee described quantum dots as 'almost perfect particles' — an assessment that captures their extraordinary combination of size-tunable optical properties, narrow emission linewidths, and compatibility with solution processing.

Dr. Zamkov was invited by Nature Nanotechnology to write a News & Views piece in response to the Nobel — a short, authoritative commentary putting the award in context and explaining what the next chapter of nanocrystal science might look like. The resulting piece argues that the quantum dot, while revolutionary, faces inherent limitations under high excitation that have prevented it from fulfilling its potential in laser diodes and other high-energy applications — and that the quantum shell architecture offers a path beyond those limitations.

Writing for Nature Nanotechnology's expert readership on the occasion of the Nobel Prize, with a co-author from MIT's Nobel-winning Bawendi group as a recent JACS co-author, Dr. Zamkov was in a unique position to both celebrate the field's recognition and argue for the direction it must next take. The piece is both a tribute to the quantum dot's scientific legacy and a case for why the quantum shell is the logical next chapter.

'Almost perfect particles' — and yet the field has not stood still. The quantum shell is what perfection looks like when you push further.

A UNIFIED RESEARCH VISION

2023: The Year the Quantum Shell Platform Matured

JACS, Chemical Communications, Nature Nanotechnology — three publications in 2023 that together tell a story of a research platform reaching maturity. The shell-in-a-shell JACS paper solved the last major technical obstacle to quantum shell performance at high excitation intensities. The Chemical Communications review established the platform's advantages comprehensively for the broader nanocrystal community. And the Nature Nanotechnology News & Views positioned the quantum shell as the natural successor to the Nobel-recognized quantum dot in a venue read by every leader in the field.

Graduate students Dulanjan Harankahage, James Cassidy, Jacob Beavon, Jiamin Huang, Niamh Brown, and Michael Montemurri are the engine of this output — their synthetic and characterization expertise, developed over years of work on quantum shells, made all three 2023 papers possible. The collaborative network they represent — connecting BGSU to MIT, Argonne, UT Dallas, and collaborators across the Anzenbacher and Sun labs — is itself a testament to the quantum shell program's scientific reputation.

The Nobel Prize going to quantum dots in 2023 was, for the Zamkov Lab, both an affirmation and a challenge. An affirmation that the scientific community recognizes the importance of quantum-confined nanocrystals. A challenge to demonstrate that the next generation of that science — the quantum shell — is already here, already working, and already expanding the horizon of what these remarkable materials can do.

2023 Publications — Zamkov Laboratory

Harankahage, D., Cassidy, J., Beavon, J., Huang, J., Brown, N., Berkinsky, D.B., Marder, A., Kayira, B., Montemurri, M., Anzenbacher, P., Jr., Schaller, R.D., Sun, L., Bawendi, M.G., Malko, A.V., Diroll, B.T., & Zamkov, M. (2023). Quantum Shell in a Shell: Engineering Colloidal Nanocrystals for a High-Intensity Excitation Regime. Journal of the American Chemical Society, 145, 13326–13334. https://doi.org/10.1021/jacs.3c03397

Beavon, J., Huang, J., Harankahage, D., Montemurri, M., Cassidy, J., & Zamkov, M. (2023). Quantum Shells versus Quantum Dots: Suppressing Auger Recombination in Colloidal Semiconductors. Chemical Communications, 59, 11337–11348. https://doi.org/10.1039/D3CC02091F

Zamkov, M. (2023). Bulk Semiconductor Nanocrystals Transform Solution-Processed Gain Media. Nature Nanotechnology, 18, 1365–1366. https://doi.org/10.1038/s41565-023-01493-1

FACULTY RESEARCH SPOTLIGHT · 2023

01  H. Peter Lu — Force, Tau, and the Nucleosome

H. Peter Lu, Ph.D.  ·  Ohio Eminent Scholar and Professor  ·  Department of Chemistry & CPS

Paper 1: Lu — 'A Missing Origin of the Tau Protein Aggregation Pathway Triggered by Thermal and Biological Forces' · Journal of Integrative Neuroscience, 22, 145–148 · 2023

DOI: 10.31083/j.jin2206145

Paper 2: Shahu, Roy Chowdhury, Lu — 'Single-Molecule Human Nucleosome Spontaneously Ruptures under the Stress of Compressive Force: A New Perspective on Gene Stability and Epigenetic Pathways' · J. Phys. Chem. B, 127, 37–44 · 2023

DOI: 10.1021/acs.jpcb.2c

TAU AND THE MISSING AGGREGATION ORIGIN

The Tau protein — whose abnormal aggregation into neurofibrillary tangles is a hallmark of Alzheimer's disease and other tauopathies — has been intensively studied for decades, yet the earliest molecular events that trigger its aggregation remain incompletely understood. In this invited article for the Journal of Integrative Neuroscience (published in a special issue on Tau Functions and Dysfunctions in Brain Disorders), Dr. Lu argues that thermal and piconewton-scale biological compressive forces — the kind of mechanical stresses that neurons experience under physiological conditions including osmotic pressure, crowding, and physical trauma — represent a missing origin of Tau aggregation that has been underappreciated by the field.

The argument builds on the Lu Lab's decade-long body of work on compressive force-induced protein rupture: the discovery that proteins can spontaneously rupture under piconewton-scale compressive forces at the single-molecule level, and that this rupture behavior is sensitive to ion composition, crowding conditions, and the mechanical environment. Applied to Tau — a protein whose extended, natively disordered structure makes it particularly susceptible to environmental perturbation — this framework suggests that force-induced structural changes could expose hydrophobic segments and initiate aggregation through a pathway entirely distinct from the chemical and concentration-dependent mechanisms most commonly studied.

This invited perspective reflects the broader significance of the Lu Lab's force-based approach: it connects single-molecule biophysics to one of medicine's most urgent unsolved problems.

NUCLEOSOME RUPTURE AND EPIGENETIC IMPLICATIONS

The second 2023 paper from the Lu Lab shifts from the disordered Tau protein to the highly structured nucleosome — the fundamental repeating unit of chromatin, in which DNA is wrapped around an octameric histone protein core. Nucleosome stability governs access to DNA for transcription, replication, and repair. Perturbation of nucleosome structure is therefore a potential mechanism for epigenetic dysregulation, yet the physical forces that can destabilize nucleosomes under physiological conditions had not been studied at the single-molecule level.

Using the Lu Lab's single-molecule AFM compressive force manipulation approach, graduate student Lalita Shahu and colleague S. Roy Chowdhury demonstrated that human nucleosomes can spontaneously rupture under piconewton-scale compressive forces — forces that are accessible under biological conditions including cellular crowding and mechanical stress. The rupture events are stochastic but reproducible, and their characteristics depend on the force magnitude and the ionic environment. The paper proposes that compressive force-induced nucleosome rupture could contribute to epigenetic changes by transiently exposing DNA to enzymatic modification machinery — a new perspective on how mechanical forces in the nucleus might influence gene expression and stability.

From Tau aggregation to nucleosome stability — the Lu Lab's 2023 work shows that compressive force is not a curiosity but a fundamental biological variable.

01  Sivaguru and Forbes — EPR Illuminates Excited State Radicals, and Dimmable Lenses Get Smarter

Jayaraman Sivaguru, Ph.D. & Malcolm D.E. Forbes, Ph.D.  ·  Distinguished University Professor / Associate Director CPS  ·  Professor & CPS Director

Paper 1: Rakhimov, Forbes, Sivaguru — 'Deciphering Mechanism of Excited State Reactivity by EPR Spectroscopy: The Case of Aryl-Maleimides' · J. Photochem. Photobiol., 18, 100207 · 2023

DOI: 10.1016/j.jpap.2023.100207

Paper 2: Baburaj, Rakhimov, Johnson, Sukhomlinova, Jockusch, Forbes, Sivaguru — 'Modulating Photochemical Properties to Enhance the Stability of Electronically Dimmable Eye Protection Devices' · Photochemistry and Photobiology, 99(4), 1222–1230 · 2023

DOI: 10.1111/php.13795

EPR AS A WINDOW INTO EXCITED STATE REACTIVITY

Electron Paramagnetic Resonance (EPR) spectroscopy is one of the most powerful tools available for detecting and characterizing radical species — molecules or molecular fragments with unpaired electrons. In photochemistry, excited states can generate radical intermediates through intersystem crossing to the triplet state, and characterizing these triplet-state radicals is often essential for understanding reaction mechanisms. Yet EPR has historically been underutilized in the mechanistic study of organic photochemical reactions, partly because the technique requires specialist expertise and partly because making the connection between EPR observables and synthetic outcomes requires a depth of photochemical understanding that is rare.

The Sivaguru-Forbes collaboration at BGSU — bringing together two faculty members whose expertise spans synthetic photochemistry and EPR spectroscopy — is uniquely positioned to bridge this gap. This Feature article in the Journal of Photochemistry and Photobiology, co-first-authored by graduate student Sarvar Aminovich Rakhimov under the joint mentorship of Professors Forbes and Sivaguru, uses the photochemistry of aryl-maleimides as the model system to demonstrate EPR's power as a mechanistic tool. The article characterizes the triplet-state radical species generated from aryl-maleimides under UV irradiation, correlating EPR observables with the photoproducts formed and the reactive pathways available — providing a mechanistic picture that complements the synthetic and ultrafast spectroscopy investigations that the Sivaguru and Tarnovsky groups conduct on the same class of compounds.

SMARTER, MORE STABLE DIMMABLE LENSES

The second 2023 paper from the Sivaguru-Forbes collaboration takes a distinctly applied direction: a joint project with Alphamicron Inc. — a Kent, Ohio company that makes electronically dimmable liquid crystal lenses used in military eyewear, welding helmets, and sports goggles — on improving the photostability of the photochromic dyes that give these devices their light-responsive properties.

Photochromic dyes — molecules that change color reversibly upon light absorption — are the active components in both photochromic lenses (like Transitions) and electronically switchable liquid crystal devices. Their practical utility depends critically on photostability: the dyes must undergo millions of switching cycles without degrading. The Sivaguru-Forbes collaboration applied the group's deep understanding of maleimide photochemistry and excited-state dynamics to identify the molecular features that govern photostability in these commercial dye systems, and to propose structural modifications that extend device lifetime.

This paper represents the kind of fundamental-to-applied connection that the CPS has always aspired to — using deep photochemical science developed in basic research to solve real problems faced by an industry partner within Ohio's manufacturing economy.

EPR reveals what ultrafast spectroscopy cannot see, and dimmable lenses need the kind of photostability knowledge that only fundamental photochemistry can provide.

03  Xiaohong Tan — The Aptamer That Mimics the His-Tag

Xiaohong Tan, Ph.D.  ·  Assistant Professor  ·  Department of Chemistry & CPS

Published in: Chemical Communications, 59, 12851–12854 · October 2023

Authors: R. Jahan, A.P. Silwal, S.K.S. Thennakoon, S.P. Arya, R.M. Postema, X. Tan

DOI: 10.1039/D3CC03349J

THE HIS-TAG PROBLEM

The polyhistidine tag — the His-tag — is one of the most ubiquitous tools in molecular biology. By appending a short sequence of six or more histidine residues to a recombinant protein, researchers can purify it rapidly and efficiently using Ni-NTA (nickel nitrilotriacetic acid) resin, to which the His-tag binds specifically through coordination chemistry with the nickel ion. Hundreds of millions of protein purifications have been performed using this system over the past three decades, and countless biochemical studies rely on His-tagged proteins.

Yet the His-tag system has a fundamental limitation for certain research applications: it is a protein-based tag that cannot be easily attached to non-protein molecules. DNA aptamers, RNA aptamers, modified nucleic acids, small-molecule drugs, and other non-protein analytes cannot carry a His-tag. If you want to purify or detect such molecules using Ni-NTA chemistry, you need a different molecular tool.

NI APT: THE NUCLEIC ACID SOLUTION

This Chemical Communications paper from the Tan Lab introduces Ni Apt — the first DNA aptamer with a characterized dissociation constant for recognizing Ni-NTA. Developed through a SELEX (Systematic Evolution of Ligands by Exponential Enrichment) campaign targeting Ni-NTA directly, the aptamer binds the Ni-NTA complex with a Kd of 106 nM — a measured affinity value, not merely a qualitative characterization.

Critically, Ni Apt can be eluted from Ni-NTA resin using imidazole or EDTA — the same elution conditions used to remove His-tagged proteins. This means Ni Apt is directly compatible with existing Ni-NTA purification workflows without any modification to reagents or instruments. Any molecule or assembly that can be conjugated to Ni Apt — a DNA strand — can now be purified or detected using standard Ni-NTA chemistry.

The paper demonstrates this capability in proof-of-concept purification experiments, establishing Ni Apt as a versatile new molecular tool for nucleic acid and non-protein analyte purification and recognition. Graduate students Raunak Jahan and Achut Prasad Silwal led the SELEX campaign and characterization work, with contributions from Siddhartha Kalpa Samadhi Thennakoon, Satya Prakash Arya, and Rick Mason Postema.

The His-tag is indispensable in protein biochemistry. Ni Apt extends that indispensability to anything that can be tethered to a DNA strand.

WHY IT MATTERS

Ni Apt is a simple tool with potentially broad utility. It enables Ni-NTA purification of aptamer-conjugated cargo — nanoparticles, small molecules, nucleic acid assemblies, modified nucleic acids — that cannot themselves carry a His-tag. It provides a nucleic acid handle for pull-down experiments, co-purification studies, and surface coating applications involving Ni-NTA substrates. And it represents a new direction for the Tan Lab's aptamer program: developing molecular tools that expand the functional capabilities of the aptamer format, rather than only targeting protein analytes.