期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 144, 期 2, 页码 769-776出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c09281
关键词
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资金
- National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) [R01 GM053148, R35 GM122603]
- Department of Energy (DOE) Computational Science Graduate Fellowship [DE-FG02-97ER25308]
The D44N mutation in the influenza A M2 channel opens the channel gate and increases proton conduction, leading to a loss of asymmetric conduction. This mutation lowers the energy barrier for His37 deprotonation in the activated state and facilitates proton flux through the Va127 tetrad. Increased hydration around the His37 tetrad enhances proton transport efficiency.
The influenza A M2 channel, a prototype for viroporins, is an acid-activated viroporin that conducts protons across the viral membrane, a critical step in the viral life cycle. Four central His37 residues control channel activation by binding subsequent protons from the viral exterior, which opens the Trp41 gate and allows proton flux to the interior. Asp44 is essential for maintaining the Trp41 gate in a closed state at high pH, resulting in asymmetric conduction. The prevalent D44N mutant disrupts this gate and opens the C-terminal end of the channel, resulting in increased conduction and a loss of this asymmetric conduction. Here, we use extensive Multiscale Reactive Molecular Dynamics (MS-RMD) and quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations with an explicit, reactive excess proton to calculate the free energy of proton transport in this M2 mutant and to study the dynamic molecular-level behavior of D44N M2. We find that this mutation significantly lowers the barrier of His37 deprotonation in the activated state and shifts the barrier for entry to the Va127 tetrad. These free energy changes are reflected in structural shifts. Additionally, we show that the increased hydration around the His37 tetrad diminishes the effect of the His37 charge on the channel's water structure, facilitating proton transport and enabling activation from the viral interior. Altogether, this work provides key insight into the fundamental characteristics of PT in WT M2 and how the D44N mutation alters this PT mechanism, and it expands understanding of the role of emergent mutations in viroporins.
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