Multiscale Simulation of HIV-1 Virion Release and Maturation

项目摘要 HIV-1病毒生命周期中的某些关键过程仍然知之甚少或不完全。这些过程 包括病毒体从受感染细胞中的释放、病毒体成熟以及病毒体内的基因组包装。 病毒体成熟的时候。这些过程是高度复杂的，涉及连续的多蛋白质和核酸 组装和拆卸，以及蛋白质介导的膜相互作用。计算模拟 因此，这些过程需要同时使用全原子（AA）和粗粒（CG）分子动力学（MD） 以一种创新的多尺度方式，以访问相关的空间和时间尺度的方法。的 Voth小组将开发并进行AA和CG模拟，以研究大型病毒蛋白复合物 与HIV-1生命周期中的这些重要问题有关。所要研究的具体过程涉及 在病毒释放和成熟过程中，特别是Gag的蛋白水解切割和衣壳组装 在病毒体（Aim 1）内，病毒体组分重组和核糖核蛋白复合物缩合， 成熟（Aim 2）和病毒体从感染细胞释放的后期动力学（Aim 3）。计算 模型开发和多尺度模拟工作将与实验研究相结合，并进行反复研究 两个领先的实验研究人员（约翰布里格斯和汉斯-格奥尔格Kräusslich）和一个独立的 资助的合作者（詹姆斯·赫尔利）。这些新颖而强大的多尺度计算机模拟-以及 与实验学家的合作努力-将提供新的洞察力的动态方面的艾滋病毒-1的释放 和成熟，这是不容易获得的实验（或计算）的努力单独。

PROJECT SUMMARY Certain key processes in the HIV-1 viral lifecycle are still poorly or incompletely understood. These processes include the release of the virion from infected cells, the virion maturation, and the genome packaging within the virion as it matures. These processes are highly complex, involving sequential multiprotein and nucleic acid assembly and disassembly, as well as protein-mediated membrane interactions. Computationally simulating these processes thus requires the use of both all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) methods in an innovative multiscale fashion in order to access the relevant spatial and temporal scales. The Voth group will develop and carry out both AA and CG simulations to study the large viral protein complexes relevant to these important problems in the HIV-1 life cycle. The specific processes to be studied are involved in the viral release and maturation processes, specifically the proteolytic cleavage of Gag and capsid assembly within the virion (Aim 1), the virion component reorganization and ribonucleoprotein complex condensation upon maturation (Aim 2), and the latter stage dynamics of virion release from infected cells (Aim 3). The computational model development and multiscale simulation efforts will be integrated and iterated with the experimental studies of two leading experimental investigators (John Briggs and Hans-Georg Kräusslich) and one independently funded collaborator (James Hurley). These novel and powerful multiscale computer simulations – and the collaborative effort with experimentalists – will provide new insight into the dynamical aspects of HIV-1 release and maturation which are not readily accessible to the experimental (or computational) efforts alone.