Voltage-Gating in the Hv1 Proton Channel: Clues from Atomistic Molecular Dynamics Simulations

Abstract

The voltage-gated proton channel, Hv1, is homologous to the voltage-sensing domain (VSD) of voltage-gated potassium (Kv) channels, but uniquely lacks a central pore domain (Ramsey et al., Nature 440, 1213, 2006; Sasaki et al., Science 312, 589, 2006). To begin to understand voltage-dependent activation in the Hv1 channel, we perform molecular dynamics simulations of a homology model for the transmembrane region of the human Hv1 in a hydrated lipid bilayer under a membrane potential. Under a depolarizing potential (positive on the intracellular side), the channel pathway exhibits a robust transmembrane hydrogen bonded water wire connecting the intracellular and extracellular sides. Under a hyperpolarizing potential, a cluster of hydrophobic side chains occludes the central region of the channel and prevents water wire formation. Assuming that a water wire plays a role in proton conduction by Hv1, these observations are consistent with experiments showing that the channel opens at depolarizing potentials. The basic side chains in the VSD S4 segment carry most of the gating charge during the activation of Kv channels. We observe translocation of the third arginine in the Hv1 S4 segment (Arg211) relative to a highly conserved phenylalanine side chain (Phe150) located at the center of the putative channel permeation pathway. Phe150 is homologous to a highly conserved Phe side chain in Kv channels, which is thought to modulate channel activation (Tao et al., Science 328, 67, 2010; Lacroix and Bezanilla, PNAS 108, 12313, 2011). Thus, our simulations suggest that these residues may be involved in voltage activation of Hv1. This work is supported by grants from the NIH (GM74637, GM86685 and GM72507) and NSF (CHE-0750175), and Teragrid resources provided by the NSF-supported NICS.