Molecular origin of the proton selectivity in the human voltage-gated proton channel

The human voltage-gated proton channel hHv1 is a ubiquitous membrane protein involved in a large range of cellular processes including proton extrusion, pH regulation, reactive oxygen species production and cancer cell proliferation. The proton channel, once activated, conducts a drastic shift in one of the four transmembrane helices aligned with the direction of the membrane potential. Mutagenesis studies have suggested that the proton selectivity of this channel is directly related to a key residue, Asp112, but the mechanism by which Asp112 controls proton selectivity remains elusive. The goal of this study is to understand the proton permeation mechanism and the associated proton selectivity of hHv1 via quantum-mechanics-based simulations of explicit proton migration over the whole channel. We computed a quantitative free energy profile characterizing the proton transport process, which, when paired with Markov state kinetics modeling, clarifies the critical involvement of Asp112 in proton selectivity.