Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.
Antimicrobial Resistance Interdisciplinary Research Group, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology Centre, Singapore 138602, Singapore.
Viruses. 2021 Mar 26;13(4):564. doi: 10.3390/v13040564.
The hepatitis B virus (HBV) capsid is an attractive drug target, relevant to combating viral hepatitis as a major public health concern. Among small molecules known to interfere with capsid assembly, the phenylpropenamides, including AT130, represent an important antiviral paradigm based on disrupting the timing of genome packaging. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that the compound increases spike flexibility and improves recovery of helical secondary structure in the spike tips. Regions of the capsid-incorporated dimer that undergo correlated motion correspond to established sub-domains that pivot around the central chassis. AT130 alters patterns of correlated motion and other essential dynamics. A new conformational state of the dimer is identified, which can lead to dramatic opening of the intradimer interface and disruption of communication within the spike tip. A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these sub-domains. Altogether, results describe a dynamical connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire core protein dimer.
乙型肝炎病毒 (HBV) 衣壳是一个有吸引力的药物靶点，与防治作为主要公共卫生问题的病毒性肝炎有关。在已知干扰衣壳组装的小分子中，苯丙烯酰胺类化合物（包括 AT130）是一种重要的抗病毒范例，其基于破坏基因组包装的时机。在这里，完整的 AT130 结合 HBV 衣壳的全原子分子动力学模拟表明，该化合物增加了刺突的灵活性，并改善了刺突尖端螺旋二级结构的恢复。衣壳整合二聚体中经历相关运动的区域与围绕中央底盘枢转的已建立的亚结构域相对应。AT130 改变了相关运动和其他基本动力学的模式。鉴定出二聚体的新构象状态，其可导致二聚体界面的剧烈打开，并破坏刺突尖端的内部通信。还发现了一个新的盐桥，即使在封闭构象下，它也可以介导刺突尖端和支点之间的接触，揭示了这些亚结构域之间直接通信的机制。总之，结果描述了单体和二聚体之间界面的动态连接，并能够映射整个核心蛋白二聚体的变构作用。
