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    Proton release from the histidine-tetrad in the M2 channel of the influenza A virus

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    Proton release from the histid ...
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    Genre
    Journal Article
    Date
    2014-11-06
    Author
    Dong, H
    Fiorin, G
    Degrado, WF
    Klein, ML
    Subject
    Histidine
    Hydrogen-Ion Concentration
    Influenza A virus
    Ion Channel Gating
    Ion Channels
    Kinetics
    Molecular Dynamics Simulation
    Protein Structure, Secondary
    Protein Structure, Tertiary
    Protons
    Quantum Theory
    Thermodynamics
    Viral Matrix Proteins
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    Permanent link to this record
    http://hdl.handle.net/20.500.12613/5286
    
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    DOI
    10.1021/jp5102225
    Abstract
    © 2014 American Chemical Society. The activity of the M2 proton channel of the influenza A virus is controlled by pH. The tautomeric state and conformation of His37, a key residue in the M2 transmembrane four-helix bundle, controls the gating of the channel. Previously, we compared the energetics and dynamics of two alternative conformations of the doubly protonated state at neutral pH, namely, a 4-fold symmetric "histidine-box" and a 2-fold symmetric "dimer-of-dimers", and proposed a multiconfiguration model for this charge state. Here, we elaborate this model by further studying configurations of the His37 tetrad in the triply protonated state and its subsequent deprotonation via quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations, starting with the aforementioned configurations, to gain information about proton release in a viral membrane environment. Interestingly, the two configurations converge under acidic pH conditions. Protons can be transferred from one charged His37 to a neighboring water cluster at the C-terminal side of the channel when the Trp41 gate is open transiently. With limited backbone expansion, the free energy barrier for proton release to the viral interior at low pH is ∼6.5 kcal/mol in both models, which is much lower than at either neutral pH or for an isolated His37 cluster without a membrane environment. Our calculations also suggest that the M2 protein would seem to exclude the entrance of anions into the central channel through a special mechanism, due to the latter's potential inhibitory effect on proton conduction. (Figure Presented).
    Citation to related work
    American Chemical Society (ACS)
    Has part
    Journal of Physical Chemistry B
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    ae974a485f413a2113503eed53cd6c53
    http://dx.doi.org/10.34944/dspace/5268
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