Multidimensional Quantum Dynamical Simulation of Infrared Spectra under Polaritonic Vibrational Strong Coupling

Recent experimental and theoretical studies demonstrate that the chemical reactivity of molecules can be modified inside an optical cavity. Here, we provide a theoretical framework for conducting multidimensional quantum simulations of the infrared (IR) spectra for molecules interacting with cavity modes. A single water molecule under polaritonic vibrational strong coupling serves as an illustrative example. Combined with accurate potential energy and dipole moment surfaces, our cavity vibrational self-consistent field/virtual state configuration interaction (cav-VSCF/VCI) approach can predict the IR spectra when the molecule is inside or outside the cavity. The spectral signatures of Rabi splittings and shifts of certain bands are found to be strongly dependent on the frequency and polarization direction of the cavity modes. Analyses of the simulated spectra show that polaritonic vibrational strong coupling can induce unconventional couplings among the molecule’s vibrational modes, suggesting that intramolecular vibrational energy transfer can be significantly accelerated by the cavity

Calculation of Electrochemical Reorganization Energies for Redox Molecules at Self-Assembled Monolayer Modified Electrodes

Electrochemical electron transfer reactions play an important role in energy conversion processes with many technological applications. Electrodes modified by self-assembled monolayers (SAMs) exhibit reduced double layer effects and are used in molecular electronics. An important quantity for calculating the electron transfer rate constant is the reorganization energy, which is associated with changes in the solute geometry and the environment. In this Letter, an approach for calculating the electrochemical reorganization energy for a redox molecule attached to or near a SAM modified electrode is presented. This integral equations formalism polarizable continuum model (IEF-PCM) approach accounts for the detailed electronic structure of the molecule, as well as the contributions from the electrode, SAM, and electronic and inertial solvent responses. The calculated total reorganization energies are in good agreement with experimental data for a series of metal complexes in aqueous solution. This approach will be useful for calculating electron transfer rate constants for molecular electrocatalysts

Role of Solvent Dynamics in Photoinduced Proton-Coupled Electron Transfer in a Phenol–Amine Complex in Solution

Photoinduced proton-coupled electron transfer (PCET) plays an essential role in a wide range of energy conversion processes. Previous experiments on a phenol–amine complex in solution provided evidence of an electron–proton transfer (EPT) excited state characterized by both intramolecular charge transfer and proton transfer from the phenol to the amine. Herein we analyze hundreds of surface hopping trajectories to investigate the role of solvent dynamics following photoexcitation to the EPT state. This solvent dynamics leads to a significant decrease in the energy gap between the ground and EPT states, thereby facilitating decay to the ground state, and generates an electrostatic environment conducive to proton transfer on the EPT state. In addition to solvent reorganization, the geometrical properties at the hydrogen-bonding interface must be suitable to allow proton transfer. These mechanistic insights elucidate the underlying fundamental physical principles of photoinduced PCET processes

Charge-Transfer Excited States and Proton Transfer in Model Guanine-Cytosine DNA Duplexes in Water

Characterization of the excited electronic states and relaxation processes in DNA systems is critical for understanding the physical basis of radiation damage. Spectroscopic studies have shown evidence of coupling between the relaxation dynamics of photoinduced charge-transfer states and interstrand proton transfer in DNA duplexes, where a deuterium isotope effect was observed for duplexes with alternating sequences but not with nonalternating sequences. We performed quantum mechanical/molecular mechanical (QM/MM) calculations of the vertical excitation energies and excited state proton potential energy curves for model DNA duplexes comprised of three guanine-cytosine pairs with alternating and nonalternating sequences in aqueous solution. Our calculations indicate that the intrastrand charge-transfer states are lower in energy for the alternating sequence than for the nonalternating sequence. The more accessible intrastrand charge-transfer states could provide a relaxation pathway coupled to interstrand proton transfer, thereby providing a possible explanation for the experimentally observed deuterium isotope effect in duplexes with alternating sequences

Tuning the Ultrafast Dynamics of Photoinduced Proton-Coupled Electron Transfer in Energy Conversion Processes

Photoinduced proton-coupled electron transfer (PCET) is essential for a wide range of energy conversion processes in chemical and biological systems. Understanding the underlying principles of photoinduced PCET at a level that allows tuning and control of the ultrafast dynamics is crucial for designing renewable and sustainable energy sources such as artificial photosynthesis devices and photoelectrochemical cells. This Perspective discusses fundamental aspects of photoinduced PCET, including the characterization of different types of excited electronic states, as well as the roles of solute and solvent dynamics, nonadiabatic transitions, proton delocalization, and vibrational relaxation. It also presents strategies for tuning and controlling the charge transfer dynamics and relaxation processes by altering the nature and positions of molecular substituents, the distance associated with electron transfer, the proton transfer interface, and the solvent properties. These insights, in conjunction with further studies, will play an important role in guiding the design of more effective energy conversion devices

Calculation of Vibrational Shifts of Nitrile Probes in the Active Site of Ketosteroid Isomerase upon Ligand Binding

The vibrational Stark effect provides insight into the roles of hydrogen bonding, electrostatics, and conformational motions in enzyme catalysis. In a recent application of this approach to the enzyme ketosteroid isomerase (KSI), thiocyanate probes were introduced in site-specific positions throughout the active site. This paper implements a quantum mechanical/molecular mechanical (QM/MM) approach for calculating the vibrational shifts of nitrile (CN) probes in proteins. This methodology is shown to reproduce the experimentally measured vibrational shifts upon binding of the intermediate analogue equilinen to KSI for two different nitrile probe positions. Analysis of the molecular dynamics simulations provides atomistic insight into the roles that key residues play in determining the electrostatic environment and hydrogen-bonding interactions experienced by the nitrile probe. For the M116C-CN probe, equilinen binding reorients an active-site water molecule that is directly hydrogen-bonded to the nitrile probe, resulting in a more linear CN‑‑H angle and increasing the CN frequency upon binding. For the F86C-CN probe, equilinen binding orients the Asp103 residue, decreasing the hydrogen-bonding distance between the Asp103 backbone and the nitrile probe and slightly increasing the CN frequency. This QM/MM methodology is applicable to a wide range of biological systems and has the potential to assist in the elucidation of the fundamental principles underlying enzyme catalysis

Computational Study of Anomalous Reduction Potentials for Hydrogen Evolution Catalyzed by Cobalt Dithiolene Complexes

The design of efficient hydrogen-evolving catalysts based on earth-abundant materials is important for developing alternative renewable energy sources. A series of four hydrogen-evolving cobalt dithiolene complexes in acetonitrile–water solvent is studied with computational methods. Co­(mnt)₂ (mnt = maleonitrile-2,3-dithiolate) has been shown experimentally to be the least active electrocatalyst (i.e., to produce H₂ at the most negative potential) in this series, even though it has the most strongly electron-withdrawing substituents and the least negative Co^III/II reduction potential. The calculations provide an explanation for this anomalous behavior in terms of protonation of the sulfur atoms on the dithiolene ligands after the initial Co^III/II reduction. One fewer sulfur atom is protonated in the Co^II(mnt)₂ complex than in the other three complexes in the series. As a result, the subsequent Co^II/I reduction step occurs at the most negative potential for Co­(mnt)₂. According to the proposed mechanism, the resulting Co^I complex undergoes intramolecular proton transfer to form a catalytically active Co^III-hydride that can further react to produce H₂. Understanding the impact of ligand protonation on electrocatalytic activity is important for designing more effective electrocatalysts for solar devices

Effects of Active Site Mutations on Specificity of Nucleobase Binding in Human DNA Polymerase η

Human DNA polymerase η (Pol η) plays a vital role in protection against skin cancer caused by damage from ultraviolet light. This enzyme rescues stalled replication forks at cyclobutane thymine–thymine dimers (TTDs) by inserting nucleotides opposite these DNA lesions. Residue R61 is conserved in the Pol η enzymes across species, but the corresponding residue, as well as its neighbor S62, is different in other Y-family polymerases, Pol ι and Pol κ. Herein, R61 and S62 are mutated to their Pol ι and Pol κ counterparts. Relative binding free energies of dATP to mutant Pol η•DNA complexes with and without a TTD were calculated using thermodynamic integration. The binding free energies of dATP to the Pol η•DNA complex with and without a TTD are more similar for all of these mutants than for wild-type Pol η, suggesting that these mutations decrease the ability of this enzyme to distinguish between a TTD lesion and undamaged DNA. Molecular dynamics simulations of the mutant systems provide insights into the molecular level basis for the changes in relative binding free energies. The simulations identified differences in hydrogen-bonding, cation−π, and π–π interactions of the side chains with the dATP and the TTD or thymine–thymine (TT) motif. The simulations also revealed that R61 and Q38 act as a clamp to position the dATP and the TTD or TT and that the mutations impact the balance among the interactions related to this clamp. Overall, these calculations suggest that R61 and S62 play key roles in the specificity and effectiveness of Pol η for bypassing TTD lesions during DNA replication. Understanding the basis for this specificity is important for designing drugs aimed at cancer treatment

Relative Binding Free Energies of Adenine and Guanine to Damaged and Undamaged DNA in Human DNA Polymerase η: Clues for Fidelity and Overall Efficiency

Human DNA polymerase η (Pol η) plays an essential protective role against skin cancer caused by cyclo­butane thymine–thymine dimers (TTDs), a frequent form of DNA damage arising from exposure to the sun. This enzyme rescues stalled replication forks at the TTDs by inserting bases opposite these DNA defects. Herein we calculate binding free energies for a free deoxy­ribose nucleotide triphosphate, dATP or dGTP, to Pol η complexed with undamaged or damaged DNA. The calculations indicate that the binding of dATP to the enzyme–DNA complex is thermodynamically favored for TTD-containing DNA over undamaged DNA, most likely because of more extensive hydrogen-bonding interactions between the TTD and the enzyme that hold the TTD more rigidly in place. The calculations also illustrate that dATP binding is thermodynamically favored over dGTP binding at both thymine positions of the TTD, most likely due to more persistent and stable hydrogen-bonding interactions between the TTD and dATP than between the TTD and dGTP. This free energy difference is slightly greater for binding at the 5′ thymine position than at the 3′ thymine position, presumably because of stabilization arising from the A:T base pair formed at the 3′ position of the TTD in the previous step of Pol η function. All of these trends in binding free energies are consistent with experimental measurements of binding strength, fidelity, processivity, and overall efficiency. The insights gained from this analysis have implications for drug design efforts aimed at modifying the binding properties of this enzyme for improving cancer chemotherapy treatments

Exploring the Role of the Third Active Site Metal Ion in DNA Polymerase η with QM/MM Free Energy Simulations

The enzyme human DNA polymerase η (Pol η) is critical for bypassing lesions during DNA replication. In addition to the two Mg²⁺ ions aligning the active site, experiments suggest that a third Mg²⁺ ion could play an essential catalytic role. Herein the role of this third metal ion is investigated with quantum mechanical/molecular mechanical (QM/MM) free energy simulations of the phosphoryl transfer reaction and a proposed self-activating proton transfer from the incoming nucleotide to the pyrophosphate leaving group. The simulations with only two metal ions in the active site support a sequential mechanism, with phosphoryl transfer followed by relatively fast proton transfer. The simulations with three metal ions in the active site suggest that the third metal ion may play a catalytic role through electrostatic interactions with the leaving group. These electrostatic interactions stabilize the product, making the phosphoryl transfer reaction more thermodynamically favorable with a lower free energy barrier relative to the activated state corresponding to the deprotonated 3′OH nucleophile, and also inhibit the subsequent proton transfer. The possibility that Mg²⁺-bound hydroxide acts as the base deprotonating the 3′OH nucleophile is also explored