Investigation of the Structure of Dimers of the Voltage-Gated Proton Channel

Abstract

Voltage-gated proton channels (Hv1) can operate functionally as monomers; however in vivo they are found as dimers which exhibit cooperative gating. The mechanism by which the cooperativity is enforced however is incompletely understood. However, it is known that removal of the tail region of the dimers, residues 234 to 255 in human Hv1, remove the cooperativity. Our investigation of the structure of the dimers and mechanism by which cooperativity in gating was enforced involved the extension of a homology model for the monomer which has been validated and reported in the literature, Chamberlin et al [1], to include a homology model of the dimer tail region based on the crystal structure of Fujiwara et al [2]. Subsequent investigation of the tail region of the closed and open state dimers were sampled using coarse-grained methods and further refined using all-atom molecular dynamics simulations. Finally, the gating path was sampled using targeted molecular dynamics simulations.[1] Chamberlin A, Qiu F, Rebolledo S, Wang YB, Noskov SY, Larsson HP. Hydrophobic plug functions as a gate in voltage-gated proton channels. P Natl Acad Sci. 2014;111:E273-E82.[2] Fujiwara Y, Kurokawa T, Takeshita K, Kobayashi M, Okochi Y, Nakagawa A, et al. The cytoplasmic coiled-coil mediates cooperative gating temperature sensitivity in the voltage-gated H+ channel Hv1. Nature Communications. 2012;3.