Gating mechanism of Hv1 studied by molecular dynamic simulations

The voltage-gated proton channel (Hv1) plays the important role in proton extrusion, pH homeostasis, sperm motility, and cancer progression. The closed-state structure of Hv1 was revealed by the X-ray crystallography. However, the opened-state structure has not been captured yet. To investigate the mechanism of proton transfer in Hv1, molecular dynamics simulations were performed with the closed-state structure of Hv1 under electric field and pH conditions. The residues arrangement on the closed-state structure revealed that the selectivity filter (Asp108) which is located in the hydrophobic layer (consists of two Phe residues 146 and 179) might prevent water penetration. In molecular dynamics simulations, we observed that the channel opened by moving up of 3 Arg on the S4 helix and a continuous hydrogen-bonded chain of water molecules (a “water wire”) went through the channel when it opened. During simulations, the open channel allowed water molecules to pass through the channel but excluded other ions. This indicates Hv1 channel is highly selective for protons. Our results clearly showed the Hv1 channel are voltage-and pH-gradient sensing.