Acid activation mechanism of the influenza A M2 proton channel
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 filt...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2017
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| Online Access: | http://hdl.handle.net/1721.1/108731 https://orcid.org/0000-0001-5255-5858 |
| _version_ | 1826216402968641536 |
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| author | Liang, Ruibin Swanson, Jessica M. J. Madsen, Jesper J. Hong, Mei DeGrado, William F. Voth, Gregory A. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Liang, Ruibin Swanson, Jessica M. J. Madsen, Jesper J. Hong, Mei DeGrado, William F. Voth, Gregory A. |
| author_sort | Liang, Ruibin |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:47:06Z |
| format | Article |
| id | mit-1721.1/108731 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:47:06Z |
| publishDate | 2017 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1087312024-06-28T14:24:46Z Acid activation mechanism of the influenza A M2 proton channel Liang, Ruibin Swanson, Jessica M. J. Madsen, Jesper J. Hong, Mei DeGrado, William F. Voth, Gregory A. Massachusetts Institute of Technology. Department of Chemistry Hong, Mei 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. United States. National Institutes of Health (R01-GM088204) 2017-05-08T13:58:47Z 2017-05-08T13:58:47Z 2016-10 2016-07 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/108731 Liang, Ruibin; Swanson, Jessica M. J.; Madsen, Jesper J.; Hong, Mei; DeGrado, William F. and Voth, Gregory A. “Acid Activation Mechanism of the Influenza A M2 Proton Channel.” Proceedings of the National Academy of Sciences 113, no. 45 (October 2016): E6955–E6964. © 2016 National Academy of Sciences. https://orcid.org/0000-0001-5255-5858 en_US http://dx.doi.org/10.1073/pnas.1615471113 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Liang, Ruibin Swanson, Jessica M. J. Madsen, Jesper J. Hong, Mei DeGrado, William F. Voth, Gregory A. Acid activation mechanism of the influenza A M2 proton channel |
| title | Acid activation mechanism of the influenza A M2 proton channel |
| title_full | Acid activation mechanism of the influenza A M2 proton channel |
| title_fullStr | Acid activation mechanism of the influenza A M2 proton channel |
| title_full_unstemmed | Acid activation mechanism of the influenza A M2 proton channel |
| title_short | Acid activation mechanism of the influenza A M2 proton channel |
| title_sort | acid activation mechanism of the influenza a m2 proton channel |
| url | http://hdl.handle.net/1721.1/108731 https://orcid.org/0000-0001-5255-5858 |
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