Hv1 is a voltage-sensitive proton channel whose main function is to extrude acid from cells. It is the most selective ion channel known and appears to be involved in a wide variety of maladies (e.g. autoimmune diseases, atherosclerosis, brain damage in ischemic stroke). Despite extensive recent research, details of the gating mechanism, proton permeation pathway, and exquisite selectivity of Hv1 remain elusive. Our group has previously developed a high-quality model of human Hv1 in its open state using a molecular dynamics simulation initiated from a homology model derived from the crystal structure of mouse Hv1 in the closed state. This model has been validated by comparison with electrophysiology data. Further investigation of the model with respect to small molecule inhibitor binding may further validate the structure and lead to the design and development of effective channel blockers. The objective of this work is to understand and improve the binding of small molecules that have been experimentally shown to block Hv1. Our approach utilizes the docking of these inhibitors to our open state model, atomistic molecular dynamics simulations, and alchemical free energy calculations. I will present preliminary results on the relative binding free energies of these Hv1 inhibitors with comparison to experimental mutagenesis and electrophysiology data.

Molecular modeling of small molecule inhibitors of the Hv1 proton channel

253rd National Meeting (2017)

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