The Mechanical Insights into Proton/Electron Transfer in Cytochrome C Oxidase Revealed by Direct Modeling of Voltage Changes in Response to Charge Separation

Abstract

The use of electrometric techniques to study time-dependent membrane potential has been used to elucidate charge motions in membrane proteins, thereby offering mechanistic insights into the function of membrane-bound pumps and transporters. The mean field macroscopic continuum approach is a usual choice of computational methods that allows one to connect the observed voltage changes to the dielectric distance obtained by solving the voltage Poisson-Boltzmann (PB-V) equation. However, correlating the observed voltage changes with the number of transferred charges and distances is challenging since the nature of the dielectric response in a protein-membrane system is complex. Recently, we introduced a new semi-microscopic coarse-graining (CG) of the voltage coupling for membrane proteins, which include the compete electrode, electrolyte, protein, membrane systems. The CG model evaluates the electrogenic events by directly simulating the external charge that flows through electrolyte solution, considering “the changes in the electrolyte distributions” between initial and final configuration of membrane proteins. This model has also provided a new avenue to measure voltage changes in Bacetrial Reactio Center by computing “the changes in electrode potentials” upon electron/proton transfer [Kim I, Charkrabarty S, Brzeninski P and Warshel A (2014) PNAS 111, 11353]. Here, we employs our CG model to give mechanical insights into electron/proton translocation within membrane in Cytochrome c Oxidase. It is found that different proton pathways can give the same elctrogenic results, and the available measurements cannot distinguish between different feasible proton/electron paths in CcO. However, consistency with the paths available upon mutations can provide a powerful insight.