QM/MM

The hybrid QM/MM (quantum mechanics/molecular mechanics) approach is a molecular simulation method that combines the strengths of ab initio QM calculations (accuracy) and MM (speed) approaches, thus allowing for the study of chemical processes in solution and in proteins. The QM/MM approach was introduced in the 1976 paper of Warshel and Levitt. They, along with Martin Karplus, won the 2013 Nobel Prize in Chemistry for "the development of multiscale models for complex chemical systems". Efficiency An important advantage of QM/MM methods is their efficiency. The cost of doing classical molecular mechanics (MM) simulations in the most straightforward case scales as O(N2), where N is the number of atoms in the system. This is mainly due to electrostatic interactions term (every particle interacts with everything else). However, use of cutoff radius, periodic pair-list updates and more recently the variations of the particle mesh Ewald (PME) method has reduced this to between

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

Murat Kiliç

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.

AMER CHEMICAL SOC2019

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

Tools to study molecules in high electric fields

Denis Bucher

EPFL2006

A QM/MM study of the optical and excited states properties of [Ru(bpy)3]2+ in water

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

Tools to study molecules in high electric fields

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

Tools to study molecules in high electric fields

A QM/MM study of the optical and excited states properties of [Ru(bpy)3]2+ in water