Does Proton Conduction in the Voltage-Gated H⁺ Channel hHv1 Involve Grotthuss-Like Hopping via Acidic Residues?

Abstract

Hv1s are ubiquitous highly selective voltage-gated proton channels involved in male fertility, immunology, and the invasiveness of certain forms of breast cancer. The mechanism of proton extrusion in Hv1 is not yet understood, while it constitutes the first step toward the design of high-affinity drugs aimed at this important pharmacological target. In this contribution, we explore the details of the mechanism via an integrative approach, using classical and QM/MM molecular dynamics simulations of a monomeric hHv1 model. We propose that protons localize in three binding sites along the channel lumen, formed by three pairs of conserved negatively charged residues lining the pore: D174/E153, D112/D185, and E119/D123. Local rearrangements, involving notably a dihedral transition of F150, a conserved phenylalanine lining the permeation pathway, appear to allow protons to hop from one acidic residue to the next through a bridging water molecule. These results constitute a first attempt at rationalizing hHv1 selectivity for H and the role played by D112 in this process. They pave the way for further quantitative characterization of H transport in hHv1.

On the control of the proton current in the voltage-gated proton channel Hv1

“…In our view and experience the challenge is not as overwhelming as might be concluded from some studies. For example, Dudev et al (13) suggested that only all-electron calculations be used for studies of Hv1, while van Keulen et al (15) presumed that EVB-type models have only been used for PT between water molecules (that might be true for some studies, e.g. ref.…”

“…Unfortunately, this study has not explored the effect of the channel opening or the effect of ionized residues beyond the limited cluster (see also discussion in ref. 15). Furthermore, the barriers for the proton movement toward the central cluster were not studied.…”

“…Finally, the authors' computatioal method has not been verified by reproducing crucial quantities such as pK a values in proteins. The work of van Keulen et al (15) has presented interesting quantum mechanics/molecular mechanics (QM/MM) and metadynamics simulations (with a classical potential) of the proton conduction process, emphasizing the Grotthuss hopping process between several acidic protein residues and intervening water molecules. However, the simulations did not converge and could not provide a free-energy profile.…”

Multiscale modeling of enzymes: QM‐cluster, QM/MM, and QM/MM/MD: A tutorial review

“…Röthlisberger and coworkers studied the proton permeation pathway of the human Hv1 (hHv1) proton channel embedded in a palmitoyl‐oleoyl‐phosphatidyl choline membrane using an integrated approach, combining QM/MM and classical MD simulations. The most crucial mechanism steps (the sequential proton jumps) have been studied using QM/MM/MD.…”

Rebuttal from Thomas E. DeCoursey

“…In a homology model of H V 1 proposing a PT chain including six carboxylates, spontaneous PT occurred whenever H 3 O + approached Asp or Glu (van Keulen et al . ).…”