激活乙型流感 M2 质子通道 (BM2)。

IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemistry Biochemistry Pub Date : 2024-11-19 Epub Date: 2024-11-03 DOI:10.1021/acs.biochem.4c00607
Zhi Yue, Jiangbo Wu, Da Teng, Zhi Wang, Gregory A Voth
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引用次数: 0

摘要

在大多数季节性流感流行期间,乙型流感病毒都会共同流行,由于其快速变异、新出现的耐药性以及对易感人群的严重影响,乙型流感病毒可导致大量人类发病和死亡。乙型流感 M2 质子通道(BM2)在病毒复制中起着至关重要的作用,但其对称质子传导和第二个组氨酸(His27)簇参与背后的机制仍不清楚。在这里,我们对野生型 BM2 和一个关键的 H27A 突变通道进行了膜支持的连续恒定 pH 分子动力学模拟,以探索它的 pH 依赖性构象转换。模拟捕捉到了第一个组氨酸(His19)质子化时的激活过程,并发现与 AM2 相比,在较低 pH 值下的转换是 His19 与预质子化的 His27 之间静电排斥的结果。最重要的是,我们通过确定 C 端部分的预激活通道水合作用,从原子水平上理解了对称质子传导。这项研究加深了我们对 BM2 功能的理解,为进一步建立明确质子转运过程的化学反应模型以及可能的抗流感药物设计工作奠定了基础。
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Activation of the Influenza B M2 Proton Channel (BM2).

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.

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来源期刊
Biochemistry Biochemistry
Biochemistry Biochemistry 生物-生化与分子生物学
CiteScore
5.50
自引率
3.40%
发文量
336
审稿时长
1-2 weeks
期刊介绍: Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.
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