Abstract
Hv1 channels are integral membrane proteins with the capacity to selectively permeate protons in a voltage and pH-dependent manner. As Hv1 lacks a pore domain, permeation must occur through the voltage-sensing domain. Previous reports propose a permeation pathway consisting in a stable water wire which allows proton to permeate by means of a Grotthuss mechanism. Our molecular dynamics simulations do not support the formation of such stable water wire since it shows a dry zone around residue N264 in the wild type and in N264 mutants. Mutations of residues D222 and N264 affects single channel conductance (determined by non-stationary noise analysis) and selectivity, suggesting that both residues are involved in the permeation pathway. Quantum dynamics simulations performed in our model of the open Ci-Hv1 wt and in silico mutants suggest that permeation occur through a proton wire involving residues D160 and D222, a process modulated by N264.Supported by Beca de Doctorado Nacional para Extranjeros de Conicyt (A.P), FONDECYT Grants 1110430 (R.L.), 1120802 (C.G.); ANILLO Grant ACT1104 (C.G.); Postdoctoral Fellowships 3140590 (G.F.C.). CINV is a Millennium Institute.
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