ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
manuscript_main.pdf (1.92 MB)
0/0

Insights on Small Molecule Binding to the Hv1 Proton Channel from Free Energy Calculations with Molecular Dynamics Simulations

preprint
submitted on 05.02.2020 and posted on 06.02.2020 by Victoria T. Lim, Andrew D. Geragotelis, Nathan M. Lim, J. Alfredo Freites, Francesco Tombola, David Mobley, Doug Tobias
Hv1 is a voltage-gated proton channel whose main function is to facilitate extrusion of protons from the cell. The development of effective channel blockers for Hv1 can lead to new therapeutics for the treatment of maladies related to Hv1 dysfunction. Although the mechanism of proton permeation in Hv1 remains to be elucidated, a series of small molecules have been discovered to inhibit Hv1. Here, we compute relative binding free energies of a prototypical Hv1 blocker on a model of human Hv1 in an open state. We use alchemical free energy perturbation techniques based on atomistic molecular dynamics simulations. The results support our proposed open state model, sheds light on the preferred tautomeric state of the blocker that binds Hv1, and lays the groundwork for future studies on adapting the blocker molecule for more effective channel blocking.

Funding

NSF Graduate Research Fellowship

NSF Grant CHE-0840513

NIH GM108889

NIH GM098973

History

Email Address of Submitting Author

limvt@uci.edu

Institution

University of California, Irvine

Country

United States

ORCID For Submitting Author

0000-0003-4030-9312

Declaration of Conflict of Interest

No conflict of interest

Exports