tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A. 2016 Oct 24. pii: 201615471. [Epub ahead of print]
[h=1]Acid activation mechanism of the influenza A M2 proton channel.[/h] Liang R[SUP]1[/SUP], Swanson JM[SUP]1[/SUP], Madsen JJ[SUP]1[/SUP], Hong M[SUP]2[/SUP], DeGrado WF[SUP]3[/SUP], Voth GA[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The homotetrameric influenza A M2 channel (AM2) is an acid-activated proton channel responsible for the acidification of the influenza virus interior, an important step in the viral lifecycle. Four histidine residues (His37) in the center of the channel act as a pH sensor and proton selectivity filter. Despite intense study, the pH-dependent activation mechanism of the AM2 channel has to date not been completely understood at a molecular level. Herein we have used multiscale computer simulations to characterize (with explicit proton transport free energy profiles and their associated calculated conductances) the activation mechanism of AM2. All proton transfer steps involved in proton diffusion through the channel, including the protonation/deprotonation of His37, are explicitly considered using classical, quantum, and reactive molecular dynamics methods. The asymmetry of the proton transport free energy profile under high-pH conditions qualitatively explains the rectification behavior of AM2 (i.e., why the inward proton flux is allowed when the pH is low in viral exterior and high in viral interior, but outward proton flux is prohibited when the pH gradient is reversed). Also, in agreement with electrophysiological results, our simulations indicate that the C-terminal amphipathic helix does not significantly change the proton conduction mechanism in the AM2 transmembrane domain; the four transmembrane helices flanking the channel lumen alone seem to determine the proton conduction mechanism.
[h=4]KEYWORDS:[/h] QM/MM; free-energy sampling; ion channel; multiscale modeling; proton conduction
PMID: 27791184 DOI: 10.1073/pnas.1615471113
[PubMed - as supplied by publisher]
[h=1]Acid activation mechanism of the influenza A M2 proton channel.[/h] Liang R[SUP]1[/SUP], Swanson JM[SUP]1[/SUP], Madsen JJ[SUP]1[/SUP], Hong M[SUP]2[/SUP], DeGrado WF[SUP]3[/SUP], Voth GA[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The homotetrameric influenza A M2 channel (AM2) is an acid-activated proton channel responsible for the acidification of the influenza virus interior, an important step in the viral lifecycle. Four histidine residues (His37) in the center of the channel act as a pH sensor and proton selectivity filter. Despite intense study, the pH-dependent activation mechanism of the AM2 channel has to date not been completely understood at a molecular level. Herein we have used multiscale computer simulations to characterize (with explicit proton transport free energy profiles and their associated calculated conductances) the activation mechanism of AM2. All proton transfer steps involved in proton diffusion through the channel, including the protonation/deprotonation of His37, are explicitly considered using classical, quantum, and reactive molecular dynamics methods. The asymmetry of the proton transport free energy profile under high-pH conditions qualitatively explains the rectification behavior of AM2 (i.e., why the inward proton flux is allowed when the pH is low in viral exterior and high in viral interior, but outward proton flux is prohibited when the pH gradient is reversed). Also, in agreement with electrophysiological results, our simulations indicate that the C-terminal amphipathic helix does not significantly change the proton conduction mechanism in the AM2 transmembrane domain; the four transmembrane helices flanking the channel lumen alone seem to determine the proton conduction mechanism.
[h=4]KEYWORDS:[/h] QM/MM; free-energy sampling; ion channel; multiscale modeling; proton conduction
PMID: 27791184 DOI: 10.1073/pnas.1615471113
[PubMed - as supplied by publisher]