M2 amphipathic helices facilitate pH-dependent conformational transition in influenza A virus
| Autor: | Afra Panahi, Hedieh Torabifard, Charles L. Brooks |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Multidisciplinary
Chemistry Amino Acid Motifs Biological Transport Hydrogen-Ion Concentration Biological Sciences Transmembrane protein Protein Structure Secondary Viral Matrix Proteins Molecular dynamics Kinetics Membrane Membrane protein Influenza A virus Proton transport Helix Amphiphile Biophysics Protons Ion channel |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 |
| Popis: | The matrix-2 (M2) protein from influenza A virus is a tetrameric, integral transmembrane (TM) protein that plays a vital role in viral replication by proton flux into the virus. The His37 tetrad is a pH sensor in the center of the M2 TM helix that activates the channel in response to the low endosomal pH. M2 consists of different regions that are believed to be involved in membrane targeting, packaging, nucleocapsid binding, and proton transport. Although M2 has been the target of many experimental and theoretical studies that have led to significant insights into its structure and function under differing conditions, the main mechanism of proton transport, its conformational dynamics, and the role of the amphipathic helices (AHs) on proton conductance remain elusive. To this end, we have applied explicit solvent constant pH molecular dynamics using the multisite λ-dynamics approach (CpHMD(MSλD)) to investigate the buried ionizable residues comprehensively and to elucidate their effect on the conformational transition. Our model recapitulates the pH-dependent conformational transition of M2 from closed to open state when the AH domain is included in the M2 construct, revealing the role of the amphipathic helices on this transition and shedding light on the proton-transport mechanism. This work demonstrates the importance of including the amphipathic helices in future experimental and theoretical studies of ion channels. Finally, our work shows that explicit solvent CpHMD(MSλD) provides a realistic pH-dependent model for membrane proteins. |
| Databáze: | OpenAIRE |
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