CHANNELS, RECEPTORS, AND ELECTRICAL SIGNALING |
Proton Transport Behavior Through the Influenza A M2 Channel: Insights from Molecular Simulation
Hanning Chen 1, Yujie Wu 1 and Gregory A. Voth 1*
1 University of Utah
* To whom correspondence should be addressed. E-mail: voth{at}chem.utah.edu.
Submitted on February 1, 2007
Revised on March 29, 2007
Accepted on 25 July 2007
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Abstract |
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The structural properties of the influenza A virus M2 trans-membrane channel in dimyristoylphosphatidylcholine (DMPC) bilayer for each of the four protonation states of the proton-gating His37 tetrad, and their effects on proton transport for this low-pH activated, highly proton-selective channel, are studied by classical molecular dynamics with the multistate empirical valence bond (MS-EVB) methodology. The excess proton permeation free energy profile and maximum ion conductance calculated from the MS-EVB simulation data combined with Poisson-Nernst-Planck (PNP) theory indicates that the triply protonated His37 state is the most likely open state via a significant side chain conformational change of the His37 tetrad. This proposed open state of M2 has a calculated proton permeation free energy barrier of 7 kcal/mol and a maximum conductance of 53 pS, compared to the experimental value of 6 pS. By contrast, the maximum conductance for Na+ is calculated to be four orders of magnitude lower, in reasonable agreement with the experimentally observed proton selectivity. The pH value to activate the channel opening is estimated to be 5.5 from dielectric continuum theory, which is also consistent with experimental results. The present study further reveals that the Ala29 residue region is the primary binding site for the anti-flu drug amantadine (AMT), probably because that domain is relatively spacious and hydrophobic. The presence of AMT is calculated to reduce the proton conductance by 99.8% due to a significant dehydration penalty of the excess proton in the vicinity of the channel-bound AMT.
Key Words:
AMT inhibition, Ion permeation, M2 channel, Proton conductance, Proton selectivity, Proton transport
