The Hv1 voltage-gated proton channel enables rapid, gated proton flux across membranes. Such proton flux may occur via a Grothuss proton ‘hopping’ mechanism as in a number of other membrane proteins and model systems. The fold of the Hv1 channel transmembrane domain is homologous to that of the voltage-sensor domain found in voltage-gated potassium, sodium, and calcium channels. This domain consists of four transmembrane helices (S1 to S4), of which S4 contains multiple positively charged arginine residues implicated in voltage sensing. We have used molecular modelling and simulation studies to explore structure/function relationships in the Hv1 channel. In particular we focus on the nature of a central water-filled pore in relation to the likely proton pathway, and the interactions of the Hv1 transmembrane domain with the surrounding lipid bilayer environment. Homology modelling of the Hv1 pore domain used the X-ray structures of the KvAP (pdb id 1ORS) and Kv1.2/2.1 chimera (pdb id 3LNM) potassium channel voltage-sensor domains as templates. Coarse-grained molecular dynamics simulations were used to predict the location of Hv1 within a phospholipid bilayer. More detailed analysis of these simulations revealed local lipid interactions with and perturbation of the bilayer by the inserted Hv1 protein (1). To gain structural insights into the proton permeation pathway in Hv1, we conducted atomistic MD simulations and analysed the extent of penetration of water into the Hv1 channel. As the template X-ray structures are thought to correspond to the ‘up’ state of the Kv voltage sensor (i.e. the state in a depolarised membrane) it is likely that our Hv1 model represents an open state of the channel. The distribution of water molecules in the simulations reveals a continuous column of waters in the central Hv1 crevice (see Figure 1). Significantly, such continuous water columns were not observed in simulations of other voltage-sensor domains (KvAP, Kv1.2/2.1, Kv1.2) which do not support proton flux. Neutralizing mutagenesis of candidate ionizable residues lining the aqueous crevice that could support Grotthuss H+ transfer failed to abrogate the proton conductance. We therefore conclude that the internal water wire is the most likely pathway for proton transfer through Hv1 (2). The importance of intraprotein water molecules for mediating H+ transfer may have relevance for understanding voltage-sensor channelopathies such as hypokalemic periodic paralysis.