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    Conformational Activation of a Transmembrane Proton Channel from Constant pH Molecular Dynamics
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    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States
    *E-mail: [email protected]
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    The Journal of Physical Chemistry Letters

    Cite this: J. Phys. Chem. Lett. 2016, 7, 19, 3961–3966
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    https://doi.org/10.1021/acs.jpclett.6b01853
    Published September 20, 2016
    Copyright © 2016 American Chemical Society
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    Abstract

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    Proton-coupled transmembrane proteins play important roles in human health and diseases; however, detailed mechanisms are often elusive. Experimentally resolving proton positions and structural details is challenging, and conventional molecular dynamics simulations are performed with preassigned and fixed protonation states. To address this challenge, here we illustrate the use of the state-of-the-art continuous constant pH molecular dynamics (CpHMD) to directly describe the activation of the M2 channel of influenza virus, for which abundant experimental data are available. Starting from the closed crystal structure, simulation reveals a pH-dependent conformational switch to an activated state that resembles the open crystal structure. Importantly, simulation affords the free energy of channel opening coupled to the titration of a histidine tetrad, thereby providing a thermodynamic mechanism for M2 activation, that is consistent with NMR data and resolves the controversy with crystal structures obtained at different pH values. This work illustrates the utility of CpHMD in offering previously unattainable conformational details and thermodynamic information for proton-coupled transmembrane channels and transporters.

    Copyright © 2016 American Chemical Society

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    Cite this: J. Phys. Chem. Lett. 2016, 7, 19, 3961–3966
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jpclett.6b01853
    Published September 20, 2016
    Copyright © 2016 American Chemical Society
    Request reuse permissions

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