Hv1: How A Voltage-sensor May Form A Channel

Abstract

Unlike canonical voltage sensor domains, which are associated with other functional domains such as channel pore domains, or more rarely enzymes, Hv1 is a voltage sensor that acts as a proton channel per se. We used modelling and simulation tools in order to investigate the molecular mechanisms of function for this recently discovered voltage-gated proton channel.As no three-dimensional structure has yet been determined for this protein, we built homology models based on the available structures of voltage-gated potassium channels. We performed coarse grain (CG) simulations of the interactions of these models with a phospholipid bilayer, enabling analysis of protein-lipid interactions. The equilibrium orientation from the CG simulations was used to aid setup of full-atom (AT) simulations with the protein embedded in a POPC bilayer. Analysis of the central pore radius and hydrogen bond interactions with water throughout the trajectories suggest that the models may capture different open conformations of Hv1. The models and simulations provide insights into a potential novel mechanism of H+ permeation involving hydronium coordination by Hv1 residues. Site-directed mutagenesis is being used to test the role of specific residues in H+ permeation through Hv1.