Center for Biophysical Modeling and Simulation and Department of Biochemistry, University of Utah, Salt Lake City, Utah, USA.
Biophys J. 2010 Nov 3;99(9):2757-65. doi: 10.1016/j.bpj.2010.08.018.
Multiscale computer simulations, employing a combination of experimental data and coarse-graining methods, are used to explore the structure of the immature HIV-1 virion. A coarse-grained (CG) representation is developed for the virion membrane shell and Gag polypeptides using molecular level information. Building on the results from electron cryotomography experiments, the simulations under certain conditions reveal the existence of an incomplete p6 hexameric lattice formed from hexameric bundles of the Gag CA domains. In particular, the formation and stability of the immature Gag lattice at the CG level requires enhanced interfacial interactions of the CA protein C-terminal domains (CTDs). An exact mapping of the CG representation back to the molecular level then allows for detailed atomistic molecular dynamics studies to confirm the existence of these enhanced CA(CTD) interactions and to probe their possible origin. The multiscale simulations further provide insight into potential CA(CTD) mutations that may disrupt or modify the Gag immature lattice assembly process in the immature HIV-1 virion.
采用多尺度计算机模拟方法，结合实验数据和粗粒化方法，研究了不成熟 HIV-1 病毒体的结构。利用分子水平的信息，为病毒包膜壳和 Gag 多肽开发了一个粗粒化（CG）表示。基于电子晶体断层扫描实验的结果，在某些条件下的模拟揭示了存在由 Gag CA 结构域的六聚体束形成的不完整的 p6 六聚晶格。特别是，CG 水平上不成熟 Gag 晶格的形成和稳定性需要增强 CA 蛋白 C 端结构域（CTD）的界面相互作用。然后，将 CG 表示精确映射回分子水平，允许进行详细的原子分子动力学研究，以确认这些增强的 CA（CTD）相互作用的存在，并探究其可能的起源。多尺度模拟还深入了解了可能破坏或改变不成熟 HIV-1 病毒体中 Gag 不成熟晶格组装过程的潜在 CA（CTD）突变。
