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Letter
Conformational Activation of a Transmembrane Proton Channel from Constant pH Molecular Dynamics Wei Chen, Yandong Huang, and Jana Shen J. Phys. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acs.jpclett.6b01853 • Publication Date (Web): 20 Sep 2016 Downloaded from http://pubs.acs.org on September 21, 2016
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The Journal of Physical Chemistry Letters
Conformational Activation of a Transmembrane Proton Channel from Constant pH Molecular Dynamics Wei Chen, Yandong Huang, and Jana Shen∗ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD E-mail:
[email protected] 1 ACS Paragon Plus Environment
The Journal of Physical Chemistry Letters
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The Journal of Physical Chemistry Letters
pH-activated transmembrane channels and transporters play important roles in human health and disease states; 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 state-of-the-art continuous constant pH molecular dynamics (CpHMD) to describe the pH-dependent conformational activation and acid-base titration of the M2 protein of influenza virus. M2 is a transmembrane channel for proton conduction. 1 During infection, the virus enters a host cell by endocytosis. The low pH condition in the endosome activates the M2 channel to conduct protons into the virion, which ultimately leads to viral uncoating. The M2 channel is a homotetramer. Each monomer contains 97 residues comprising an extracellular N-terminal segment (residues 1-23), a transmembrane segment (residues 24-46, termed M2TM), and an intracellular C-terminal segment (residues 47-97). M2TM has been demonstrated to reproduce the electrophysiological and pharmacological features of the full-length M2. 2 X-ray structures, 3–5 solution 6 and solid-state NMR (ssNMR) models 7–9 showed that M2TM, is a left-handed four-helix parallel bundle (Fig. 1A) with the N-terminal half forming an aqueous pore lined by Val27, Ala30, Ser31 and Gly34, mutations of which cause resistance to drug amantadine. 10 In the middle of M2TM, His37 forms a tetrad that accepts protons at low pH, 7,11,12 inducing the Trp41 gate located below to open and activate the channel. 6,13 Using M2TM in liposome, Cross and coworkers determined the stepwise pK a values of the histidine tetrad to be 8.2, 8.2, 6.3 and
