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Updated: Jun 8, 2025

Co-immunoprecipitation of the Mouse Mx1 Protein with the Influenza A Virus Nucleoprotein
Published on: April 21, 2015
Activation of the Influenza B M2 Proton Channel (BM2)
Zhi Yue1, Jiangbo Wu1, Da Teng1
1Department of Chemistry, Chicago Center for Theoretical Chemistry, James Frank Institute, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, United States.
Abstract:
Influenza B viruses have cocirculated during most seasonal flu epidemics and can cause significant human morbidity and mortality due to their rapid mutation, emerging drug resistance, and severe impact on vulnerable populations. The influenza B M2 proton channel (BM2) plays an essential role in viral replication, but the mechanisms behind its symmetric proton conductance and the involvement of a second histidine (His27) cluster remain unclear. Here we performed membrane-enabled continuous constant-pH molecular dynamics simulations on wildtype BM2 and a key H27A mutant channel to explore its pH-dependent conformational switch. Simulations captured the activation as the first histidine (His19) protonates and revealed the transition at lower pH values compared to AM2 is a result of electrostatic repulsions between His19 and preprotonated His27. Crucially, we provided an atomic-level understanding of the symmetric proton conduction by identifying preactivating channel hydration in the C-terminal portion. This research advances our understanding of the function of BM2 function and lays the groundwork for further chemically reactive modeling of the explicit proton transport process as well as possible antiflu drug design efforts.
Insights
Influenza B virus M2 channel (BM2) proton transport mechanisms were simulated. Researchers found His27 influences BM2 activation pH and identified key hydration sites for proton conduction, aiding antiviral drug design.
Area of Science:
- Biophysics
- Virology
- Structural Biology
Background:
- Influenza B viruses cause significant morbidity and mortality.
- The influenza B M2 proton channel (BM2) is crucial for viral replication.
- BM2's proton conductance mechanisms and the role of His27 are not fully understood.
Purpose of the Study:
- To investigate the pH-dependent conformational switch of wildtype BM2 and an H27A mutant.
- To elucidate the atomic-level mechanisms of symmetric proton conduction in BM2.
Main Methods:
- Membrane-enabled continuous constant-pH molecular dynamics simulations.
- Simulations were performed on wildtype BM2 and a His27 to Alanine (H27A) mutant channel.
Main Results:
- BM2 activation occurs upon His19 protonation.
- Lower activation pH compared to AM2 is due to electrostatic repulsion between His19 and His27.
- Preactivating channel hydration in the C-terminal portion was identified as crucial for proton conduction.
Conclusions:
- This study provides an atomic-level understanding of BM2 function.
- Findings lay the groundwork for reactive modeling of proton transport and antiviral drug design.
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