tetano
Editor, Senior Moderator
J Phys Chem Lett. 2013 Sep 19;4(18):3067-3071. Epub 2013 Aug 28.
Exploring Histidine Conformations in the M2 Channel Lumen of the Influenza A Virus at Neutral pH via Molecular Simulations.
Dong H, Fiorin G, Degrado WF, Klein ML.
Source
Institute for Computational Molecular Science, Temple University , 1900 North 12th Street, Philadelphia, Pennsylvania 19122-6078, United States.
Abstract
The pH-regulated M2 proton channel from the influenza A virus has a His-tetrad in its transmembrane (TM) domain that is essential for proton conduction. At neutral pH, the tetrad has been observed in two distinct configurations, the "His-box" and "dimer-of-dimers", with similar backbone structures suggesting competing models for proton conduction. Here, we propose that both conformations can play a role. In support of this hypothesis, we used molecular dynamics simulations based on density functional theory to simulate the M2-TM domain and force-field-based simulations to estimate the relevant free-energy barriers. Both configurations are stable on accessible simulation time scales, and transitions between them occur faster than the millisecond time scale of proton conduction. Moreover, the deprotonation energy is too high for spontaneous conduction, consistent with their occurrence in the low-current regime. Our computations support a multiconfiguration model with different population levels, thereby connecting experimental data obtained under different conditions.
PMID:
24069512
[PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/24069512
Exploring Histidine Conformations in the M2 Channel Lumen of the Influenza A Virus at Neutral pH via Molecular Simulations.
Dong H, Fiorin G, Degrado WF, Klein ML.
Source
Institute for Computational Molecular Science, Temple University , 1900 North 12th Street, Philadelphia, Pennsylvania 19122-6078, United States.
Abstract
The pH-regulated M2 proton channel from the influenza A virus has a His-tetrad in its transmembrane (TM) domain that is essential for proton conduction. At neutral pH, the tetrad has been observed in two distinct configurations, the "His-box" and "dimer-of-dimers", with similar backbone structures suggesting competing models for proton conduction. Here, we propose that both conformations can play a role. In support of this hypothesis, we used molecular dynamics simulations based on density functional theory to simulate the M2-TM domain and force-field-based simulations to estimate the relevant free-energy barriers. Both configurations are stable on accessible simulation time scales, and transitions between them occur faster than the millisecond time scale of proton conduction. Moreover, the deprotonation energy is too high for spontaneous conduction, consistent with their occurrence in the low-current regime. Our computations support a multiconfiguration model with different population levels, thereby connecting experimental data obtained under different conditions.
PMID:
24069512
[PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/24069512