Effect of Ionization State on Voltage-Sensor Structure in Resting State of the Hv1 Channel

Abstract

Voltage-gated proton-selective channels (Hv1) mediate proton extrusion during intracellular acidification. Hv1 is gated by the proton electrochemical gradient. Intracellular ionizable residues in Hv1 have been proposed to serve as proton-binding sites for pH-dependent gating, but detailed descriptions remain unclear. Here, molecular dynamics (MD) simulations were performed to investigate the effect of ionization states of charged residues on the X-ray structure of Hv1. Modification of the protonation state of acidic residues affected the resting conformation of Hv1 by disrupting salt bridges between S4 and the other segments. Upon protonation, conformational changes enabled the displacement of the S4 arginines toward the extracellular side and increased the mobility of hydrophobic residues at the gate. The aqueous crevice was considerably wider with increased hydration in the pore. Solvation free energies of the pore residues were low at the extra- and intracellular entrances, whereas the narrowest region exhibited the energy barrier for water translocation. Our MD data showed that water molecules in the upper and lower pore oriented differently. In neutral pH, the pore water oriented its dipole pointing away from the voltage-sensing domain center, whereas the opposite direction of the water dipole was observed in acidic pH.

Water, Protons, and the Gating of Voltage-Gated Potassium Channels

“…Although it is not generally considered that this challenges the standard model, it is difficult to see why it does not; it provides a similar path that could be taken by protons [32]. H v 1 is the subject of multiple studies, and there is still no general agreement on the gating mechanism [29,[33][34][35][36][37][38]. It appears that protons contribute to the gating current [39].…”

Exploring polyamine interactions and binding pockets in SARS-CoV-2 ORF3a

“…The protein structure of ORF3a dimer with PDB ID code 7KJR [ 7 ] was used for MD simulations. The detailed steps for studying protein-membrane systems with MD simulations were performed as described in our previous work [ 31 ]. Briefly, prior to insertion of the protein into explicit lipid models, we determined the optimal spatial position of the protein in a membrane by calculating the solvation free energy along the z-axis [ 32 ].…”

Virtual Issue on Ion Channels and Ion Permeation

“…A few articles investigated specific systems where H + are implicated. Boonamnaj and Sompornpisut use MD simulations to investigate the effect of ionization states of charged residues on the X-ray structure of the voltage-gated proton-selective channel Hv1, observing that modification of the protonation state of acidic residues disrupts salt bridges between S4 and the other segments and affects the conformation of the channel. Kariev and Green use ab initio computations to show that protonation of residues is predicted to affect the response of the voltage-sensing domain and the gating mechanism of potassium channels.…”