Theory and SImulation of Viral Replication

项目摘要 病毒是在生物体的活细胞内复制的感染因子， 了解控制病毒复制的基本分子机制，因为它们执行许多复杂的 物理和化学过程，从原子尺度的现象，如量子化学， 键断裂到大规模过程，如蛋白质自组装。这些过程从根本上 多尺度，因为它们跨越从分子到介观的时间和长度尺度。例如在 病毒颗粒成熟，组特异性抗原多蛋白（Gag）的蛋白水解裂解释放衣壳 结构域蛋白（CA），随后重新组装成富勒烯衣壳。我们的首要目标是研究 利用理论、基于物理的建模和计算机， 模拟 这项提案集中在病毒生命周期的五个关键方面：（1）先天免疫传感器如何像 TRIM 5 α通过组装成六边形图案来限制病毒感染 网格以物理地笼住病毒核心并向衣壳发出降解信号，（2）材料和物理 外壳的性质，包住和保护病毒基因组，（3）pH值的化学特征， 门控孔分布在整个衣壳表面，（4）发生大规模的形态学变化， （5）SARS-CoV-2病毒融合过程中刺突蛋白的构象动力学。 我们的策略是开发多尺度模拟方法，将一个长度尺度上的分子行为与 下一个将开发粗粒度（CG）方法和简化表示模型， 生物过程的基本物理学，并且在模拟大规模病毒感染方面也具有计算效率。 流程.全原子（AA）模拟将用于准确探测蛋白质构象动力学。债券 将使用混合量子-经典方法来描述分裂和形成，例如，量子 力学/分子力学（QM/MM）计算。这些模拟将作为基础， 开发基于混合动力学蒙特卡罗分子动力学（MC/MD）的反应CG模型， 量子现象到CG尺度。 对病毒复制的计算预测将与领先的 结构生物学家和生物化学家。总的来说，这些研究的见解将广泛影响以下领域： 分子模拟、病毒学和计算生物物理学。这些研究的结果有可能 帮助开发新的治疗策略来对抗病毒感染。

PROJECT SUMMARY Viruses are infectious agents that replicate inside the living cells of an organism, and it remains critical to understand the basic molecular mechanisms that govern viral replication, as they perform numerous complex physical and chemical processes ranging from atomic-scale phenomena, such as the quantum chemistry of bond cleavage to large-scale processes, such as protein self-assembly. These processes are fundamentally multiscale since they span time and length scales from the molecular to the mesoscopic. For instance, during viral particle maturation, proteolytic cleavage of the group-specific antigen polyprotein (Gag) releases capsid domain proteins (CA) that subsequently reassemble into a fullerene capsid. Our overarching goal is to study the molecular processes involved in viral replication using theory, physics-based modeling, and computer simulations. This proposal focuses on five key aspects of the viral life cycle: (1) how innate immune sensors like the tripartite motif containing protein 5 α (TRIM5α) restrict viral infection by assembling into hexagonally-patterned lattices to physically cage the viral core and signal the capsid for degradation, (2) the material and physical properties of the capsid shell that encases and protects the viral genome, (3) the chemical features of pH- gated pores distributed throughout the capsid surface, (4) the large-scale morphological changes that occur during virion maturation, and (5) the conformational dynamics of spike proteins in SARS-CoV-2 virion fusion. Our strategy is to develop multiscale simulation methods to link molecular behavior at one length-scale to the next. Coarse-grained (CG) methods and reduced representation models will be developed that retain the essential physics of the biological process and are also computationally efficient to simulate large-scale viral processes. All-atom (AA) simulations will be used to accurately probe protein conformational dynamics. Bond cleavage and formation will be described using mixed quantum-classical approaches, e.g., quantum mechanical/molecular mechanics (QM/MM) calculations. These simulations will serve as the basis for developing reactive CG models based on hybrid kinetic Monte Carlo molecular dynamics (MC/MD) to link quantum phenomena to the CG scale. Computational predictions on viral replication will be tested and validated in collaboration with leading structural biologists and biochemists. Collectively, insights from these studies will broadly impact the fields of molecular simulation, virology, and computational biophysics. Findings from these studies have the potential to aid in the development of new therapeutic strategies to combat viral infection.