Molecular Dynamics Simulation Studies of Ion Permeation Pathways and Energetics in the Hv1 Proton Channel

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). In Hv1, which normally dimerizes, but also functions in its monomeric form, the VSD also contains the proton conduction pathway (Koch et al., PNAS 105, 9111, 2008; Tombola et al., Neuron 58, 546, 2008). To understand the proton conduction mechanism in Hv1, we performed prolonged atomistic molecular dynamics simulations in the 1-μs time scale of different homology models for the transmembrane region of the human Hv1 in a hydrated lipid bilayer. We characterize the unique structural features of each model and analyze the hydration of the channel. To begin to elucidate energetics of ion permeation, we employ quantum mechanics/molecular mechanics (QM/MM) simulations, to model proton transfer in the channel. This study offers insight into the structural determinants of proton selectivity as well as the mechanism of proton transport. This work is supported by grants from the NIH (GM74737, GM86685 and GM098973).