Microscopic Picture of the Solvent Reorganization During Electron Transfer to Flavin in Water

The redox potential of molecular species is largely modulated by its molecular environment so that a change of the environment will lead to a different redox potential. However, a detailed molecular picture of reorganization of the environment upon reduction is still unclear. To unravel the details of the solvent reorganization during electron transfer, we have performed density functional theory-based molecular dynamics (DFT-MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations of the reduction of lumiflavin. Previously, we have calculated the reduction free energy curves of the redox half reactions of lumiflavin in water as a function of the instantaneous gap energy (Delta E) (J. Chem. Theory Comput. 2013, 9, 3889-3899). In this work, we focus on finding the changes in the solvent environment that correlate with this Delta E reaction coordinate. Comparing the QM/MM simulations, in which the solvent is modeled with an empirical force field, with the (full) DFT-MD simulations, we find that the response through electronic polarization plays a significant role in the latter case. Also a small charge transfer between flavin and solvent is observed in the full DFT treatment. As a result, we find only in the case of the QM/MM model a strong correlation between Delta E and the (pairwise computed) electrostatic potential (ESP) at the flavin due to the solvent. By analyzing the contribution of the ESP at the flavin per solvent molecule, we cannot only distinguish between the different modes of hydration by solvent molecules that coordinate at the hydrophilic and hydrophobic sides of the flavin molecule but also quantify their contribution to the reorganization free energy by measuring the ESP fluctuations per solvent molecule.

Tools to study molecules in high electric fields

Denis Bucher

This thesis describes the application of the quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello methodology to two systems of high biological interest: (a) The potassium channel KcsA from Streptomyces lividans and (b) The DNA repair enzyme EndoIV of E.Coli. bacteria. The two studies provide new insights into key biological mechanisms such as the ion selectivity of cell membranes and the DNA repair system. Special emphasize was put on the importance of polarization effects in these systems. Most classical simulations performed today are based on non-polarizable force fields which only include electronic polarization implicitly. This thesis work shows that non-polarizable potential functions do not describe accurately the permeation in ion channels in all cases. Indeed, most current biomolecular packages were developed for the study of globular proteins and have only recently been applied to the study of ion channels. The importance of ion/protein induced polarization effects in the KcsA channel was demonstrated using different computational approaches: first, the fluctuations in the electronic density were studied (Chapter 3). Second, the quantum mechanical electrostatic potential inside the channel was compared to the corresponding result of popular MM force fields (Chapter 4). Third, the coordination geometry of the K+ and Na+ ions inside the channel was investigated (Chapter 5). It was found that the binding geometry of Na+ observed in classical simulations differs significantly from the results of ab initio simulations. In Chapter 6, the protonation state of the Glu71 and Asp80 residues is investigated. While errors due to a neglect of induced polarization effects amount to typically ∼0.1e/per atom, errors in the attribution of a protonation state cause an error of 1e. Thus a correct description of protonation states of the Glu71 and Asp80 residues is crucial. These residues located in the vicinity of the conductive pore in the KcsA K+ channel were found to share dynamically a proton, which may directly influence ion conduction. The proton exchange was found to be faster (sub-picosecond) than the ion translocation (nanosecond). It is important to stress that this mechanism could not have been seen by a classical study. The influence of Glu-71 on the ionic conduction was subsequently confirmed by structural and electrophysiological experiments (Cordero-Morales, Cuello et al. 2006; Cordero-Morales, Cuello et al. 2006), which indicate that Glu71 acts as a voltage sensor regulating the gating of the channel. Chapter 7 deals with an investigation of the catalytic efficiency of the DNA repair enzyme Endonuclease IV. The enzyme catalyses the hydrolysis of DNA at the phosphodiester bond of apurinic/apyrimidinic (AP) sites. The computer model highlighted the importance of electrostatic interactions in the stabilization of the phosphorane transition state. A revised catalytic mechanism is proposed for the phosphohydrolysis which involves a proton transfer. Our results also suggest that the reaction rate is not controlled by the chemical step, which is in agreement with experimental results.

EPFL2006

Explicit solvent simulations of the aqueous oxidation potential and reorganization energy for neutral molecules: Gas phase, linear solvent response, and non-linear response contributions

Jeremy Samuel Arey, Jennifer Guerard, Marianne Seijo, Peter Rudolf Tentscher

First principles simulations were used to predict aqueous one-electron oxidation potentials (E-ox) and associated half-cell reorganization energies (lambda(aq)) for aniline, phenol, methoxybenzene, imidazole, and dimethylsulfide. We employed quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations of the oxidized and reduced species in an explicit aqueous solvent, followed by EOM-IP-CCSD computations with effective fragment potentials for diabatic energy gaps of solvated clusters, and finally thermodynamic integration of the non-linear solvent response contribution using classical MD. A priori predicted E-ox and lambda(aq) values exhibit mean absolute errors of 0.17 V and 0.06 eV, respectively, compared to experiment. We also disaggregate E-ox into several well-defined free energy properties, including the gas phase adiabatic free energy of ionization (7.73 to 8.82 eV), the solvent-induced shift in the free energy of ionization due to linear solvent response (-2.01 to -2.73 eV), and the contribution from non-linear solvent response (-0.07 to -0.14 eV). The linear solvent response component is further apportioned into contributions from the solvent-induced shift in vertical ionization energy of the reduced species (Delta VIEaq) and the solvent-induced shift in negative vertical electron affinity of the ionized species (Delta NVEA(aq)). The simulated Delta VIEaq and Delta NVEA(aq) are found to contribute the principal sources of uncertainty in computational estimates of E-ox and lambda(aq). Trends in the magnitudes of disaggregated solvation properties are found to correlate with trends in structural and electronic features of the solute. Finally, conflicting approaches for evaluating the aqueous reorganization energy are contrasted and discussed, and concluding recommendations are given.

Royal Soc Chemistry2015

Tools to study molecules in high electric fields

Denis Bucher

EPFL2006

Explicit solvent simulations of the aqueous oxidation potential and reorganization energy for neutral molecules: Gas phase, linear solvent response, and non-linear response contributions

Jeremy Samuel Arey, Jennifer Guerard, Marianne Seijo, Peter Rudolf Tentscher

Royal Soc Chemistry2015