乙型肝炎病毒衣壳组装及其二态性的多尺度建模

StephenW

乙型肝炎病毒衣壳组装及其二态性的多尺度建模
Farzaneh Mohajerani 1 , Botond Tyukodi 1 2 , Christopher J Schlicksup 3 , Jodi A Hadden-Perilla 4 , Adam Zlotnick 3 , Michael F Hagan 1
隶属关系
隶属关系

    1
    Martin A. Fisher 物理学院，布兰代斯大学，沃尔瑟姆，马萨诸塞州 02453，美国。
    2
    Babeş-Bolyai 大学物理系，400084 Cluj-Napoca，罗马尼亚。
    3
    印第安纳大学分子和细胞生物化学系，布卢明顿，印第安纳州 47405，美国。
    4
    特拉华大学化学与生物化学系，纽瓦克，特拉华州 19716，美国。

    PMID：36054910 DOI：10.1021/acsnano.2c02119

抽象的

乙型肝炎病毒 (HBV) 是一种地方性慢性病毒，每年导致 80 万人死亡。作为 HBV 生命周期的核心，病毒核心有一个由单个蛋白质的多个拷贝组装而成的蛋白质衣壳。衣壳蛋白采用不同（准等效）构象形成含有 180 或 240 种蛋白质的二十面体衣壳：在 Caspar-Klug 命名法中，T = 3 或 T = 4。 HBV衣壳组装已成为最近开发的抗病毒药物的重要靶标；然而，控制HBV二态性的组装途径和机制仍不清楚。我们使用粗粒度模型描述了 HBV 组装的计算机模拟，该模型具有从完整 HBV 衣壳的全原子分子动力学模拟中学习的参数，但在计算上是易于处理的。使用所得模型进行的动态模拟再现了 HBV 组装途径和产物的实验观察结果。通过构建马尔可夫状态模型并采用过渡路径理论，我们确定了导致 T = 3、T = 4 和其他实验观察到的衣壳形态的路径。分析表明，低HBV衣壳弯曲模量促进衣壳多态性，其中控制多态性的关键因素是构象能量景观和蛋白质-蛋白质结合亲和力。

关键词：乙型肝炎病毒；抗病毒药物；计算建模；多尺度模拟；自组装；病毒衣壳。

StephenW

Multiscale Modeling of Hepatitis B Virus Capsid Assembly and Its Dimorphism
Farzaneh Mohajerani  1 , Botond Tyukodi  1   2 , Christopher J Schlicksup  3 , Jodi A Hadden-Perilla  4 , Adam Zlotnick  3 , Michael F Hagan  1
Affiliations
Affiliations

    1
    Martin A. Fisher School of Physics, Brandeis University, Waltham, Massachusetts 02453, United States.
    2
    Department of Physics, Babeş-Bolyai University, 400084 Cluj-Napoca, Romania.
    3
    Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, Indiana 47405, United States.
    4
    Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, United States.

    PMID: 36054910 DOI: 10.1021/acsnano.2c02119

Abstract

Hepatitis B virus (HBV) is an endemic, chronic virus that leads to 800000 deaths per year. Central to the HBV lifecycle, the viral core has a protein capsid assembled from many copies of a single protein. The capsid protein adopts different (quasi-equivalent) conformations to form icosahedral capsids containing 180 or 240 proteins: T = 3 or T = 4, respectively, in Caspar-Klug nomenclature. HBV capsid assembly has become an important target for recently developed antivirals; nonetheless, the assembly pathways and mechanisms that control HBV dimorphism remain unclear. We describe computer simulations of the HBV assembly, using a coarse-grained model that has parameters learned from all-atom molecular dynamics simulations of a complete HBV capsid and yet is computationally tractable. Dynamical simulations with the resulting model reproduce experimental observations of HBV assembly pathways and products. By constructing Markov state models and employing transition path theory, we identify pathways leading to T = 3, T = 4, and other experimentally observed capsid morphologies. The analysis shows that capsid polymorphism is promoted by the low HBV capsid bending modulus, where the key factors controlling polymorphism are the conformational energy landscape and protein-protein binding affinities.

Keywords: Hepatitis B virus; antivirals; computational modeling; multiscale simulations; self-assembly; viral capsid.

StephenW

https://doi.org/10.1101/2022.02.23.481637