Puja Goyal

Application of the SCC-DFTB method to neutral and protonated water clusters and bulk water

The self-consistent charge density functional tight-binding (SCC-DFTB) method has been actively employed to study proton-transfer processes in biological systems. Recent studies in the literature employing SCC-DFTB reported that the method favors the Zundel form of the hydrated proton over the Eigen form, both in gas-phase water clusters and in bulk water, in disagreement with both higher-level calculations and experimental data. In this work, we explore the performance of SCC-DFTB for protonated gas-phase water clusters and bulk water (the latter both with and without an excess proton) with a modified O-H repulsive potential reported in our earlier work and with on-site third-order expansion of the DFT energy. Our results show that, with the proper set of published parameters, SCC-DFTB does correctly favor the Eigen form of the hydrated proton as compared to the Zundel form, both in gas-phase clusters and in the bulk; the amphiphilic character of the hydrated proton discussed in the literature has also been observed. The analyses do, however, bring forth remaining limitations in terms of the solvation structure around the hydrated proton as well as the structure of bulk water, which can guide future improvements of the method.

Molecular simulation of water and hydration effects in different environments: challenges and developments for DFTB based models.

We discuss the description of water and hydration effects that employs an approximate density functional theory, DFTB3, in either a full QM or QM/MM framework. The goal is to explore, with the current formulation of DFTB3, the performance of this method for treating water in different chemical environments, the magnitude and nature of changes required to improve its performance, and factors that dictate its applicability to reactions in the condensed phase in a QM/MM framework. A relatively minor change (on the scale of kBT) in the O–H repulsive potential is observed to substantially improve the structural properties of bulk water under ambient conditions; modest improvements are also seen in dynamic properties of bulk water. This simple change also improves the description of protonated water clusters, a solvated proton, and to a more limited degree, a solvated hydroxide. By comparing results from DFTB3 models that differ in the description of water, we confirm that proton transfer energetics are adequately described by the standard DFTB3/3OB model for meaningful mechanistic analyses. For QM/MM applications, a robust parametrization of QM-MM interactions requires an explicit consideration of condensed phase properties, for which an efficient sampling technique was developed recently and is reviewed here. The discussions help make clear the value and limitations of DFTB3 based simulations, as well as the developments needed to further improve the accuracy and transferability of the methodology.

Role of the Active Site Guanine in the glmS Ribozyme Self-Cleavage Mechanism: Quantum Mechanical/Molecular Mechanical Free Energy Simulations

The glmS ribozyme catalyzes a self-cleavage reaction at the phosphodiester bond between residues A-1 and G1. This reaction is thought to occur by an acid–base mechanism involving the glucosamine-6-phosphate cofactor and G40 residue. Herein quantum mechanical/molecular mechanical free energy simulations and pKa calculations, as well as experimental measurements of the rate constant for self-cleavage, are utilized to elucidate the mechanism, particularly the role of G40. Our calculations suggest that an external base deprotonates either G40(N1) or possibly A-1(O2′), which would be followed by proton transfer from G40(N1) to A-1(O2′). After this initial deprotonation, A-1(O2′) starts attacking the phosphate as a hydroxyl group, which is hydrogen-bonded to deprotonated G40, concurrent with G40(N1) moving closer to the hydroxyl group and directing the in-line attack. Proton transfer from A-1(O2′) to G40 is concomitant with attack of the scissile phosphate, followed by the remainder of the cleavage reaction. A mechanism in which an external base does not participate, but rather the proton transfers from A-1(O2′) to a nonbridging oxygen during nucleophilic attack, was also considered but deemed to be less likely due to its higher effective free energy barrier. The calculated rate constant for the favored mechanism is in agreement with the experimental rate constant measured at biological Mg2+ ion concentration. According to these calculations, catalysis is optimal when G40 has an elevated pKa rather than a pKa shifted toward neutrality, although a balance among the pKa’s of A-1, G40, and the nonbridging oxygen is essential. These results have general implications, as the hammerhead, hairpin, and twister ribozymes have guanines at a similar position as G40.

Changing hydration level in an internal cavity modulates the proton affinity of a key glutamate in cytochrome c oxidase

Significance Cytochrome c oxidase is an important proton pump that utilizes the chemical energy released by oxygen reduction to generate the transmembrane proton concentration gradient. A conserved glutamate residue has been proposed to play a key role in proton pumping, although factors that control the timing and destination of proton transfers by this residue remain poorly understood. By integrating results from multiple computational methodologies, we propose a mechanism in which changes in local hydration and electrostatic interactions regulate the proton affinity of this key residue and, as a result, proton transfer activities. The results highlight the functional significance of local protein motions and hydration state of internal cavities. Cytochrome c oxidase contributes to the transmembrane proton gradient by removing two protons from the high-pH side of the membrane each time the binuclear center active site is reduced. One proton goes to the binuclear center, whereas the other is pumped to the low-pH periplasmic space. Glutamate 286 (Glu286) has been proposed to serve as a transiently deprotonated proton donor. Using unrestrained atomistic molecular dynamics simulations, we show that the size of and water distribution in the hydrophobic cavity that holds Glu286 is controlled by the protonation state of the propionic acid of heme a3, a group on the proton outlet pathway. Protonation of the propionate disrupts hydrogen bonding to two side chains, allowing a loop to swing open. Continuum electrostatics and atomistic free-energy perturbation calculations show that the resultant changes in hydration and electrostatic interactions lower the Glu proton affinity by at least 5 kcal/mol. These changes in the internal hydration level occur in the absence of major conformational transitions and serve to stabilize needed transient intermediates in proton transport. The trigger is not the protonation of the Glu of interest, but rather the protonation of a residue ∼10 Å away. Thus, unlike local water penetration to stabilize a new charge, this finding represents a specific role for water molecules in the protein interior, mediating proton transfers and facilitating ion transport.

Nonadiabatic Dynamics of Photoinduced Proton-Coupled Electron Transfer in a Solvated Phenol–Amine Complex

Photoinduced concerted electron-proton transfer (EPT), denoted photo-EPT, is important for a wide range of energy conversion processes. Transient absorption and Raman spectroscopy experiments on the hydrogen-bonded p-nitrophenylphenol-t-butylamine complex, solvated in 1,2-dichloroethane, suggested that this complex may undergo photo-EPT. The experiments probed two excited electronic states that were interpreted as an intramolecular charge transfer (ICT) state and an EPT state. Herein mixed quantum mechanical/molecular mechanical nonadiabatic surface hopping dynamics is used to investigate the relaxation pathways following photoexcitation. The potential energy surface is generated on the fly with a semiempirical floating occupation molecular orbital complete active space configuration interaction method for the solute molecule and a molecular mechanical force field for the explicit solvent molecules. The free energy curves along the proton transfer coordinate illustrate that proton transfer is thermodynamically and kinetically favorable on the lower-energy excited state but not on the higher-energy excited state, supporting the characterization of these states as EPT and ICT, respectively. The nonadiabatic dynamics simulations indicate that the population decays from the ICT state to the EPT state in ∼100 fs and from the EPT state to the ground state on the slower time scale of ∼1 ps, qualitatively consistent with the experimental measurements. For ∼54% of the trajectories, the proton transfers from the phenol to the amine in ∼400 fs on the EPT state and then transfers back to the phenol rapidly upon decay to the ground state. Thus, these calculations augment the original interpretation of the experimental data by providing evidence of proton transfer on the EPT state prior to decay to the ground state. The fundamental insights obtained from these simulations are also relevant to other photo-EPT processes.

Proton Quantization and Vibrational Relaxation in Nonadiabatic Dynamics of Photoinduced Proton-Coupled Electron Transfer in a Solvated Phenol-Amine Complex.

Nonadiabatic dynamics simulations of photoinduced proton-coupled electron transfer (PCET) in a phenol-amine complex in solution were performed. The electronic potential energy surfaces were generated on-the-fly with a hybrid quantum mechanical/molecular mechanical approach that described the solute with a multiconfigurational method in a bath of explicit solvent molecules. The transferring hydrogen nucleus was represented as a quantum mechanical wave function calculated with grid-based methods, and surface hopping trajectories were propagated on the adiabatic electron-proton vibronic surfaces. Following photoexcitation to the excited S1 electronic state, the overall decay to the ground vibronic state was found to be comprised of relatively fast decay from a lower proton vibrational state of S1 to a highly excited proton vibrational state of the ground S0 electronic state, followed by vibrational relaxation within the S0 state. Proton transfer can occur either on the highly excited proton vibrational states of S0 due to small environmental fluctuations that shift the delocalized vibrational wave functions or on the low-energy proton vibrational states of S1 due to solvent reorganization that alters the asymmetry of the proton potential and reduces the proton transfer barrier. The isotope effect arising from replacing the transferring hydrogen with deuterium is predicted to be negligible because hydrogen and deuterium behave similarly in both types of proton transfer processes. Although an isotope effect could be observed for other systems, in general the absence of an isotope effect does not imply the absence of proton transfer in photoinduced PCET systems. This computational approach is applicable to a wide range of other photoinduced PCET processes.

DFTB3 Parametrization for Copper: The Importance of Orbital Angular Momentum Dependence of Hubbard Parameters

We report the parametrization of a density functional tight binding method (DFTB3) for copper in a spin-polarized formulation. The parametrization is consistent with the framework of 3OB for main group elements (ONCHPS) and can be readily used for biological applications that involve copper proteins/peptides. The key to our parametrization is to introduce orbital angular momentum dependence of the Hubbard parameter and its charge derivative, thus allowing the 3d and 4s orbitals to adopt different sizes and responses to the change of charge state. The parametrization has been tested by applying to a fairly broad set of molecules of biological relevance, and the properties of interest include optimized geometries, ligand binding energies, and ligand proton affinities. Compared to the reference QM level (B3LYP/aug-cc-pVTZ, which is shown here to be similar to the B97-1 and CCSD(T) results, in terms of many properties of interest for a set of small copper containing molecules), our parametrization generally gives reliable structural properties for both Cu(I) and Cu(II) compounds, although several exceptions are also noted. For energetics, the results are more accurate for neutral ligands than for charged ligands, likely reflecting the minimal basis limitation of DFTB3; the results generally outperform NDDO based methods such as PM6 and even PBE with the 6-31+G(d,p) basis. For all ligand types, single-point B3LYP calculations at DFTB3 geometries give results very close (∼1–2 kcal/mol) to the reference B3LYP values, highlighting the consistency between DFTB3 and B3LYP structures. Possible further developments of the DFTB3 model for a better treatment of transition-metal ions are also discussed. In the current form, our first generation of DFTB3 copper model is expected to be particularly valuable as a method that drives sampling in systems that feature a dynamical copper binding site.

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.

Copper Oxidation/Reduction in Water and Protein: Studies with DFTB3/MM and VALBOND Molecular Dynamics Simulations

We apply two recently developed computational methods, DFTB3 and VALBOND, to study copper oxidation/reduction processes in solution and protein. The properties of interest include the coordination structure of copper in different oxidation states in water or in a protein (plastocyanin) active site, the reduction potential of the copper ion in different environments, and the environmental response to copper oxidation. The DFTB3/MM and VALBOND simulation results are compared to DFT/MM simulations and experimental results whenever possible. For a copper ion in aqueous solution, DFTB3/MM results are generally close to B3LYP/MM with a medium basis, including both solvation structure and reduction potential for Cu(II); for Cu(I), however, DFTB3/MM finds a two-water coordination, similar to previous Born-Oppenheimer molecular dynamics simulations using BLYP and HSE, whereas B3LYP/MM leads to a tetrahedron coordination. For a tetraammonia copper complex in aqueous solution, VALBOND and DFTB3/MM are consistent in terms of both structural and dynamical properties of solvent near copper for both oxidation states. For copper reduction in plastocyanin, DFTB3/MM simulations capture the key properties of the active site, and the computed reduction potential and reorganization energy are in fair agreement with experiment, especially when the periodic boundary condition is used. Overall, the study supports the value of VALBOND and DFTB3(/MM) for the analysis of fundamental copper redox chemistry in water and protein, and the results also help highlight areas where further improvements in these methods are desirable.

Role of active site conformational changes in photocycle activation of the AppA BLUF photoreceptor

Significance Photoreceptor proteins play a critical role in the light regulation of physiologically essential processes, including color vision, circadian rhythms, and photomovement. Photoexcitation of a chromophore bound to the photoreceptor protein leads to local conformational changes that propagate to distal regions of the protein and thereby drive vital chemical and physical changes. Understanding the fundamental mechanisms of these proteins is important for engineering systems that use light to control biological processes with high spatiotemporal resolution. In this study, computer simulations of a photoreceptor protein provide valuable insights into the active site conformations prior to and following photoexcitation. The position of a certain tryptophan residue, as well as the hydrogen-bonding pattern, is shown to impact the activation and efficiency of this photoreceptor. Blue light using flavin adenine dinucleotide (BLUF) proteins are essential for the light regulation of a variety of physiologically important processes and serve as a prototype for photoinduced proton-coupled electron transfer (PCET). Free-energy simulations elucidate the active site conformations in the AppA (activation of photopigment and puc expression) BLUF domain before and following photoexcitation. The free-energy profile for interconversion between conformations with either Trp104 or Met106 closer to the flavin, denoted Trpin/Metout and Trpout/Metin, reveals that both conformations are sampled on the ground state, with the former thermodynamically favorable by ∼3 kcal/mol. These results are consistent with the experimental observation of both conformations. To analyze the proton relay from Tyr21 to the flavin via Gln63, the free-energy profiles for Gln63 rotation were calculated on the ground state, the locally excited state of the flavin, and the charge-transfer state associated with electron transfer from Tyr21 to the flavin. For the Trpin/Metout conformation, the hydrogen-bonding pattern conducive to the proton relay is not thermodynamically favorable on the ground state but becomes more favorable, corresponding to approximately half of the configurations sampled, on the locally excited state. The calculated energy gaps between the locally excited and charge-transfer states suggest that electron transfer from Tyr21 to the flavin is more facile for configurations conducive to proton transfer. When the active site conformation is not conducive to PCET from Tyr21, Trp104 can directly compete with Tyr21 for electron transfer to the flavin through a nonproductive pathway, impeding the signaling efficiency.