havior in PCET 3400 5.3. Adiabatic and Nonadiabatic PCET Interpreted in the Context of the Schrodinger Equation and the Born−Oppenheimer (Adiabatic) Approximation 3404 5.3.1. Quantum-State Dynamics of PCET Systems and the Underlying Potential (Free) Energy Surfaces 3404 5.3.2. Investigating Coupled Electronic−Nuclear Dynamics and Deviations from the Adiabatic Approximation in PCET Systems via a Simple Model 3408 5.3.3. Formulation and Representations of Electron−Proton States 6. Extension of Marcus Theory to Proton and Atom Transfer Reactions 6.1. Extended Marcus Theory for Electron, Proton, and Atom Transfer Reactions 6.2. Implications of the Extended Marcus Theory: Brønsted Slope, Kinetic Isotope Effect, and Cross-Relation 7. Beyond Marcus Theory: Nuclear Tunneling and Structural Constraints on PCET 8. Proton-Activated Electron Transfer: A Special Case of Separable and Coupled PT and ET 9. Dogonadze−Kuznetsov−Levich (DKL) Model of PT/HAT and Connections with ET and PCET Theories 10. Borgis−Hynes (BH) Theory for PT and HAT 10.1. Dynamical Regimes of the BH Theory 10.2. Splitting and Coupling Fluctuations 10.3. Reaction Rate Constant 10.4. Analytical Rate Constant Expressions in Limiting Regimes 11. Cukier Theory of PCET 11.1. Double-Adiabatic and Two-Dimensional Approaches 11.2. Reorganization and Solvation Free Energy in ET, PT, and EPT 11.3. Generalization of the Theory and Connections between PT, PCET, and HAT 12. Soudackov−Hammes-Schiffer (SHS) Theory of PCET 12.1. Regarding System Coordinates and Interactions: Hamiltonians and Free Energies 12.2. Electron−Proton States, Rate Constants, and Dynamical Effects 12.3. Note on the Kinetic Isotope Effect in PCET 12.4. Distinguishing between HAT and Concerted PCET Reactions 12.5. Electrochemical PCET 13. Conclusions and Prospects Appendix A Appendix B Associated Content Supporting Information

ConspectusThe image is not the thing. Just as a pipe rendered in an oil painting cannot be smoked, quantum mechanical coupling pathways rendered on LCDs do not convey electrons. The aim of this Account is to examine some of our recent discoveries regarding biological electron transfer (ET) and transport mechanisms that emerge when one moves beyond treacherous static views to dynamical frameworks.Studies over the last two decades introduced both atomistic detail and macromolecule dynamics to the description of biological ET. The first model to move beyond the structureless square-barrier tunneling description is the Pathway model, which predicts how protein secondary motifs and folding-induced through-bond and through-space tunneling gaps influence kinetics. Explicit electronic structure theory is applied routinely now to elucidate ET mechanisms, to capture pathway interferences, and to treat redox cofactor electronic structure effects. Importantly, structural sampling of proteins provides an understanding of how dynamics may change the mechanisms of biological ET, as ET rates are exponentially sensitive to structure. Does protein motion average out tunneling pathways? Do conformational fluctuations gate biological ET? Are transient multistate resonances produced by energy gap fluctuations? These questions are becoming accessible as the static view of biological ET recedes and dynamical viewpoints take center stage.This Account introduces ET reactions at the core of bioenergetics, summarizes our team’s progress toward arriving at an atomistic-level description, examines how thermal fluctuations influence ET, presents metrics that characterize dynamical effects on ET, and discusses applications in very long (micrometer scale) bacterial nanowires. The persistence of structural effects on the ET rates in the face of thermal fluctuations is considered. Finally, the flickering resonance (FR) view of charge transfer is presented to examine how fluctuations control low-barrier transport among multiple groups in van der Waals contact. FR produces exponential distance dependence in the absence of tunneling; the exponential character emerges from the probability of matching multiple vibronically broadened electronic energies within a tolerance defined by the rms coupling among interacting groups. FR thus produces band like coherent transport on the nanometer length scale, enabled by conformational fluctuations. Taken as a whole, the emerging context for ET in dynamical biomolecules provides a robust framework to design and interpret the inner workings of bioenergetics from the molecular to the cellular scale and beyond, with applications in biomedicine, biocatalysis, and energy science.

Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a small-molecule approach is often viewed as insufficient to achieve high affinity and specificity. Here we show that small molecules can enable potent inhibition by targeting key waters. The M2 proton channel of influenza A is the target of the antiviral drugs amantadine and rimantadine. Structural studies of drug binding to the channel using X-ray crystallography have been limited because of the challenging nature of the target, with the one previously solved crystal structure limited to 3.5 Å resolution. Here we describe crystal structures of amantadine bound to M2 in the Inward conformation (2.00 Å), rimantadine bound to M2 in both the Inward (2.00 Å) and Inward (2.25 Å) conformations, and a spiro-adamantyl amine inhibitor bound to M2 in the Inward conformation (2.63 Å). These X-ray crystal structures of the M2 proton channel with bound inhibitors reveal that ammonium groups bind to water-lined sites that are hypothesized to stabilize transient hydronium ions formed in the proton-conduction mechanism. Furthermore, the ammonium and adamantyl groups of the adamantyl-amine class of drugs are free to rotate in the channel, minimizing the entropic cost of binding. These drug-bound complexes provide the first high-resolution structures of drugs that interact with and disrupt networks of hydrogen-bonded waters that are widely utilized throughout nature to facilitate proton diffusion within proteins.

Extracellular appendages of the dissimilatory metal-reducing bacterium Shewanella oneidensis MR-1 were recently shown to sustain currents of 1010 electrons per second over distances of 0.5 microns [El-Naggar et al., Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 18127]. However, the identity of the charge localizing sites and their organization along the “nanowire” remain unknown. We use theory to predict redox cofactor separation distances that would permit charge flow at rates of 1010 electrons per second over 0.5 microns for voltage biases of ≤1V, using a steady-state analysis governed by a non-adiabatic electron transport mechanism. We find the observed currents necessitate a multi-step hopping transport mechanism, with charge localizing sites separated by less than 1 nm and reorganization energies that rival the lowest known in biology.

Throughout biology, amyloids are key structures in both functional proteins and the end product of pathologic protein misfolding. Amyloids might also represent an early precursor in the evolution of life because of their small molecular size and their ability to self-purify and catalyze chemical reactions. They also provide attractive backbones for advanced materials. When β-strands of an amyloid are arranged parallel and in register, side chains from the same position of each chain align, facilitating metal chelation when the residues are good ligands such as histidine. High-resolution structures of metalloamyloids are needed to understand the molecular bases of metal-amyloid interactions. Here we combine solid-state NMR and structural bioinformatics to determine the structure of a zinc-bound metalloamyloid that catalyzes ester hydrolysis. The peptide forms amphiphilic parallel β-sheets that assemble into stacked bilayers with alternating hydrophobic and polar interfaces. The hydrophobic interface is stabilized by apolar side chains from adjacent sheets, whereas the hydrated polar interface houses the Zn-binding histidines with binding geometries unusual in proteins. Each Zn has two bis-coordinated histidine ligands, which bridge adjacent strands to form an infinite metal-ligand chain along the fibril axis. A third histidine completes the protein ligand environment, leaving a free site on the Zn for water activation. This structure defines a class of materials, which we call metal-peptide frameworks. The structure reveals a delicate interplay through which metal ions stabilize the amyloid structure, which in turn shapes the ligand geometry and catalytic reactivity of Zn.