All-atom molecular dynamics of the HBV capsid reveals insights into biological function and cryo-EM resolution limits.
All-atom molecular dynamics of the HBV capsid reveals insights into biological function and cryo-EM resolution limits.
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DOI：
10.7554/elife.32478
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发表时间：
2018-04-27
期刊：
影响因子：
7.7
通讯作者：
Schulten K
中科院分区：
文献类型：
--
作者：
Hadden JA;Perilla JR;Schlicksup CJ;Venkatakrishnan B;Zlotnick A;Schulten K
乙型肝炎病毒衣壳是一个很有前途的治疗靶点。实验表明，衣壳必须具有柔性才能发挥作用；然而，在缺乏二十面体对称约束的情况下，衣壳的结构和动力学并没有得到彻底的表征。在这里，利用全原子分子动力学模拟来研究无对称偏差的衣壳，从而研究衣壳的灵活性及其对生物功能和低温电镜分辨率限制的影响。仿真结果证实了柔性，并揭示了不对称畸变的倾向。衣壳对离子种类的影响提示了一种调节细胞信号显示的机制，并暗示衣壳的三角形孔是信号暴露的位置。使用模拟构象进行的理论图像重建表明衣壳的灵活性如何限制低温电镜的分辨率。总的来说，目前的工作提供了超越实验方法的功能见解，并提出了关于二十面体病毒衣壳结构研究中的不对称性的重要考虑。
The hepatitis B virus capsid represents a promising therapeutic target. Experiments suggest the capsid must be flexible to function; however, capsid structure and dynamics have not been thoroughly characterized in the absence of icosahedral symmetry constraints. Here, all-atom molecular dynamics simulations are leveraged to investigate the capsid without symmetry bias, enabling study of capsid flexibility and its implications for biological function and cryo-EM resolution limits. Simulation results confirm flexibility and reveal a propensity for asymmetric distortion. The capsid’s influence on ionic species suggests a mechanism for modulating the display of cellular signals and implicates the capsid’s triangular pores as the location of signal exposure. A theoretical image reconstruction performed using simulated conformations indicates how capsid flexibility may limit the resolution of cryo-EM. Overall, the present work provides functional insight beyond what is accessible to experimental methods and raises important considerations regarding asymmetry in structural studies of icosahedral virus capsids.