与AT130结合的HBV衣壳的全原子MD模拟显示二级和三级结构变化

StephenW

All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery
by Carolina Pérez-Segura
1 [OrcID] , Boon Chong Goh
2 [OrcID] and Jodi A. Hadden-Perilla
1,* [OrcID]
1
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
2
Antimicrobial Resistance Interdisciplinary Research Group, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology Centre, Singapore 138602, Singapore
*
Author to whom correspondence should be addressed.
Academic Editor: Stefan G. Sarafianos
Viruses 2021, 13(4), 564; https://doi.org/10.3390/v13040564
Received: 8 February 2021 / Revised: 15 March 2021 / Accepted: 23 March 2021 / Published: 26 March 2021
(This article belongs to the Special Issue Capsid-Targeting Antivirals and Host Factors)
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Abstract
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.
Keywords: hepatitis B virus; HBV; virus capsid; core protein allosteric modulator; CpAM; phenylpropenamide; AT130; molecular dynamics simulations; physical virology, computational virology

StephenW

与AT130结合的HBV衣壳的全原子MD模拟显示二级和三级结构变化和变构机制
卡罗莱纳州佩雷斯·塞古拉（CarolinaPérez-Segura）
1 [OrcID]，Boon Chong Goh
2 [OrcID]和Jodi A. Hadden-Perilla
1，* [OrcID]
1个
特拉华大学，纽瓦克，化学与生物化学系，德国19716
2个
新加坡-马萨诸塞州技术研究所研究与技术中心联盟抗菌素耐药性跨学科研究小组，新加坡138602，新加坡
*
应与之联系的作者。
学术编辑：Stefan G. Sarafianos
病毒2021，13（4），564; https://doi.org/10.3390/v13040564
收到：2021年2月8日/修订：2021年3月15日/接受：2021年3月23日/发布：2021年3月26日
（本文属于针对衣壳的特刊，针对抗病毒药和宿主因子）
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引文出口
抽象的
乙型肝炎病毒（HBV）衣壳是一种有吸引力的药物靶标，与抗击病毒性肝炎有关，是主要的公共卫生问题。在已知会干扰衣壳装配的小分子中，包括AT130在内的苯基丙烯酰胺代表着一种重要的抗病毒范式，它基于破坏基因组包装的时机。在这里，完整的AT130结合的HBV衣壳的全原子分子动力学模拟表明，该化合物增加了尖峰的柔韧性并改善了尖峰尖端螺旋二级结构的回收率。衣壳结合的二聚体经历相关运动的区域对应于围绕中央机架枢转的已建立子域。 AT130改变相关运动和其他基本动力的模式。确定了二聚体的新构象状态，这可能导致二聚体内界面急剧打开并破坏尖峰内的通讯。还发现了一种新型的盐桥，即使在闭合构象下，它也可以介导尖峰尖端和支点之间的接触，揭示了跨这些子域的直接通讯机制。总而言之，结果描述了二聚体界面之间和二聚体界面之间的动态联系，并能够绘制遍历整个核心蛋白二聚体的变构图。
关键词：乙型肝炎病毒；乙肝病毒;病毒衣壳核心蛋白变构调节剂； CpAM；苯丙烯酰胺AT130；分子动力学模拟；物理病毒学，计算病毒学

StephenW

https://www.mdpi.com/1999-4915/13/4/564/htm