Thermodynamics and Mechanism of the Membrane Permeation of Hv1 Channel Blockers.

The Journal of Membrane Biology
Victoria T LimDouglas J Tobias

Abstract

The voltage-gated proton channel Hv1 mediates efflux of protons from the cell. Hv1 integrally contributes to various physiological processes including pH homeostasis and the respiratory burst of phagocytes. Inhibition of Hv1 may provide therapeutic avenues for the treatment of inflammatory diseases, breast cancer, and ischemic brain damage. In this work, we investigate two prototypical Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI), and 5-chloro-2-guanidinobenzimidazole (GBIC), from an experimentally screened class of guanidine derivatives. Both compounds block proton conduction by binding the same site located on the intracellular side of the channel. However, when added to the extracellular medium, the compounds strongly differ in their ability to inhibit proton conduction, suggesting substantial differences in membrane permeability. Here, we compute the potential of mean force for each compound to permeate through the membrane using atomistic molecular dynamics simulations with the adaptive biasing force method. Our results rationalize the putative distinction between these two blockers with respect to their abilities to permeate the cellular membrane.

References

Jan 1, 1974·The Journal of Membrane Biology·J M Diamond, Y Katz
Apr 4, 2003·Nature·Thomas E DeCourseyVladimir V Cherny
May 4, 2004·Chembiochem : a European Journal of Chemical Biology·Grégori GerebtzoffAnna Seelig
Oct 12, 2005·Proceedings of the National Academy of Sciences of the United States of America·J Alfredo FreitesStephen H White
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Jan 5, 2006·Journal of the American Chemical Society·Justin L MacCallum, D Peter Tieleman
Mar 24, 2006·Nature·I Scott RamseyDavid E Clapham
Mar 25, 2006·Science·Mari SasakiYasushi Okamura
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Mar 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Sudha Dorairaj, Toby W Allen
Apr 17, 2008·The Journal of Chemical Physics·Eric DarveAndrew Pohorille
May 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Seok-Yong LeeRoderick Mackinnon
Jun 28, 2008·Proceedings of the National Academy of Sciences of the United States of America·Hans P KochH Peter Larsson
Jul 19, 2008·The Journal of Physical Chemistry. B·Libo LiToby W Allen
Jul 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Boris MussetThomas E DeCoursey
Mar 17, 2009·Biochemical and Biophysical Research Communications·Yoshifumi OkochiYasushi Okamura
Apr 18, 2009·Proceedings of the National Academy of Sciences of the United States of America·I Scott RamseyDavid E Clapham
Oct 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Deri MorganThomas E DeCoursey
May 26, 2010·The Journal of Physical Chemistry. B·Jeffery B KlaudaRichard W Pastor
Jun 15, 2010·Nature Structural & Molecular Biology·I Scott RamseyDavid E Clapham
Oct 19, 2010·Physical Chemistry Chemical Physics : PCCP·Hannes G WallnoeferChristofer S Tautermann
Nov 3, 2011·The Journal of Physical Chemistry. B·Victor Vivcharuk, Yiannis N Kaznessis
Nov 15, 2011·Proceedings of the National Academy of Sciences of the United States of America·Michael J HarmsBertrand García-Moreno
Dec 27, 2011·Neuron·Thomas K Berger, Ehud Y Isacoff
Mar 6, 2012·Nature Neuroscience·Long-Jun WuDavid E Clapham
Nov 14, 2012·Journal of Chemical Information and Modeling·K VanommeslaegheA D MacKerell
Nov 14, 2012·Journal of Chemical Information and Modeling·K Vanommeslaeghe, A D MacKerell
May 28, 2013·BMC Immunology·Xiang ZhuNives Zimmermann
Sep 27, 2013·Physical Chemistry Chemical Physics : PCCP·Kevin E Riley, Pavel Hobza
Feb 4, 2014·Antioxidants & Redox Signaling·Tamara SeredeninaKarl-Heinz Krause
Feb 11, 2014·Biophysical Journal·Igor VorobyovToby W Allen
Mar 4, 2014·Nature Structural & Molecular Biology·Kohei TakeshitaAtsushi Nakagawa
Apr 30, 1998·The Journal of Physical Chemistry. B·A D MacKerellM Karplus
Jun 10, 2014·Proceedings of the National Academy of Sciences of the United States of America·Liang HongFrancesco Tombola
Nov 27, 2014·Proceedings of the National Academy of Sciences of the United States of America·Elayne HondaresMelania Capasso
Mar 27, 2015·Protein Science : a Publication of the Protein Society·Carolyn A FitchLawrence P McIntosh
Feb 11, 2014·Journal of Chemical Theory and Computation·Jeffrey ComerChristophe Chipot
Dec 10, 2013·Journal of Chemical Theory and Computation·Giulia ParisioAlberta Ferrarini

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