Toward molecular models of proton pumping: Challenges, methods and relevant applications

Abstract

Motivated by several long-lasting mechanistic questions for biomolecular proton pumps, we have engaged in developing hybrid quantum mechanical/molecular mechanical (QM/MM) methods that allow an efficient and reliable description of long-range proton transport in transmembrane proteins. In this review, we briefly discuss several relevant issues: the need to develop a "multi-scale" generalized solvent boundary potential (GSBP) for the analysis of chemical events in large trans-membrane proteins, approaches to validate such a protocol, and the importance of improving the flexibility of QM/MM Hamiltonian. Several recent studies of model and realistic protein systems are also discussed to help put the discussions into context. Collectively, these studies suggest that the QM/MM-GSBP framework based on an approximate density functional theory (SCC-DFTB) as QM holds the promise to strike the proper balance between computational efficiency, accuracy and generality. With additional improvements in the methodology and recent developments by others, especially powerful sampling techniques, this "multi-scale" framework will be able to help unlock the secrets of proton pumps and other biomolecular machines.proton pumping, QM/MM simulations, SCC-DFTB, microscopic pK a , multi-scale simulations

Molecular Simulation of Water and Hydration Effects in Different Environments: Challenges and Developments for DFTB Based Models

“…By comparing results using DFTB3 models that differ in the description of water, we are able to confirm that proton transfer energetics are adequately described by the standard DFTB3/3OB model for meaningful mechanistic analyses. This finding is consistent with the approach that we have been employing to calibrate the DFTB models over the years for proton transfer studies, 12 , 63 , 92 , 186 , 187 i.e., focusing on proton affinities, p K a values, and relative solvation free energies of different protonation states (including hydroxide 12 ). Along this line, it is clear from the discussions here that a careful consideration of QM-MM interaction is also essential, and a robust parametrization requires an explicit consideration of condensed phase properties rather than gas phase clusters only.…”

Microscopic mechanisms that govern the titration response and p K a values of buried residues in staphylococcal nuclease mutants

“…S13). Considering the limited amount of quantitative comparison between simulation and experiment regarding the properties of the conformational ensembles, and limitations of the PB/LRA approach in the presence of major structural transitions, it remains difficult to conclude which force field(s) studied here leads to results that are closer to reality. Indeed, what we aim to promote through this study is extensive comparisons between computation and experiment for multiple types of observables beyond the often targeted p K a values, so that we are confident that molecular simulations are able to “obtain the right answers for the right reasons” …”

Stabilization of Different Types of Transition States in a Single Enzyme Active Site: QM/MM Analysis of Enzymes in the Alkaline Phosphatase Superfamily

“…19 Therefore, it is imperative to explicitly carry out computational analysis of phosphate monoester hydrolysis in the AP enzymes using our QM/MM approach. Due to the highly charged nature of phosphate monoesters, such calculations have not become possible until very recently due to the development of an improved QM-MM electrostatic model 37,38 for SCC-DFTB based QM/MM simulations.…”