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Gianti E , Delemotte L , Klein ML , Carnevale V
On the role of water density fluctuations in the inhibition of a proton channel
Proc Natl Acad Sci U S A. 2016 Dec 27;113(52) :E8359-e8368
PMID: 27956641    PMCID: PMC5206518   
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Hv1 is a transmembrane four-helix bundle that transports protons in a voltage-controlled manner. Its crucial role in many pathological conditions, including cancer and ischemic brain damage, makes Hv1 a promising drug target. Starting from the recently solved crystal structure of Hv1, we used structural modeling and molecular dynamics simulations to characterize the channel's most relevant conformations along the activation cycle. We then performed computational docking of known Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and analogs. Although salt-bridge patterns and electrostatic potential profiles are well-defined and distinctive features of activated versus nonactivated states, the water distribution along the channel lumen is dynamic and reflects a conformational heterogeneity inherent to each state. In fact, pore waters assemble into intermittent hydrogen-bonded clusters that are replaced by the inhibitor moieties upon ligand binding. The entropic gain resulting from releasing these conformationally restrained waters to the bulk solvent is likely a major contributor to the binding free energy. Accordingly, we mapped the water density fluctuations inside the pore of the channel and identified the regions of maximum fluctuation within putative binding sites. Two sites appear as outstanding: One is the already known binding pocket of 2GBI, which is accessible to ligands from the intracellular side; the other is a site located at the exit of the proton permeation pathway. Our analysis of the waters confined in the hydrophobic cavities of Hv1 suggests a general strategy for drug discovery that can be applied to any ion channel.
1091-6490 Gianti, Eleonora Delemotte, Lucie Klein, Michael L Carnevale, Vincenzo P01 GM055876/GM/NIGMS NIH HHS/United States S10 OD020095/OD/NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. United States Proc Natl Acad Sci U S A. 2016 Dec 27;113(52):E8359-E8368. doi: 10.1073/pnas.1609964114. Epub 2016 Dec 12.