Theory and SImulation of Viral Replication

病毒复制理论与模拟

• 批准号: 10793013
• 负责人: Alvin Yu
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10793013
• 关键词: 2019-nCoV; ACE2; Adopted; Arginine; Award; Behavior; Binding; Biological Process; Biophysical Process; Biophysics; COVID-19; Capsid; Cells; Cellular biology; Charge; Chemicals; Collaborations; Complex; Computer Simulation; Cryo-electron tomography; Data; Development; Disease; Elements; Event; Extracellular Space; Fullerenes; Genetic Materials; Goals; Grain; HIV; HIV Infections; Heterogeneity; Hybrids; Image; Immune; Infectious Agent; Innate Immune Response; Kinetics; Knowledge; Length; Letters; Life Cycle Stages; Link; Macaca mulatta; Mechanical Stress; Methodology; Methods; Modeling; Molecular; Molecular Conformation; Morphology; Nucleotides; Organism; Pattern; Peptide Hydrolases; Peptides; Phase; Physics; Phytic Acid; Play; Polyproteins; Process; Property; Protein Conformation; Proteins; Quantum Mechanics; Research; Reverse Transcription; Reverse Transcription Induction; Roentgen Rays; Role; Rupture; SARS-CoV-2 transmission; Sampling; Series; Signal Transduction; Statistical Data Interpretation; Structural Biologist; Structure; Surface; System; TRIM Motif; Tertiary Protein Structure; Testing; Time; Transcription Process; United States National Institutes of Health; Viral; Viral Genome; Virion; Virus; Virus Diseases; Virus Replication; Work; career; combat; dimer; gag Gene Products; inhibitor therapy; insight; models and simulation; molecular dynamics; molecular mechanics; molecular modeling; molecular scale; novel therapeutic intervention; pandemic disease; particle; physical property; quantum; quantum chemistry; receptor; receptor binding; self assembly; sensor; simulation; small molecule; structural biology; theories; trafficking; virology; virus genetics

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.

项目摘要 病毒是在生物体中复制生物内复制的传染剂，对 了解控制病毒复制的基本分子机制，因为它们执行了许多复杂 物理和化学过程范围从原子级现象，例如 键切割到大规模过程，例如蛋白质自组装。这些过程从根本上是 多尺度，因为它们跨越了时间和长度从分子到介质的尺度。例如，期间 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capsid 域蛋白（CA）随后重新组装成富勒烯衣壳。我们的总体目标是学习 使用理论，基于物理的建模和计算机参与病毒复制的分子过程 模拟。 该提案重点介绍病毒生命周期的五个关键方面：（1）先天免疫传感器如何喜欢 包含蛋白5α（TRIM5α）的三方基序通过组装成六角形图案来限制病毒感染 晶格可以物理封封病毒核并发出capid降解的信号，（2）材料和物理 包围和保护病毒基因组的衣壳壳的特性，（3）pH-的化学特征 分布在整个衣壳表面的门控孔，（4）发生的大规模形态变化 在病毒体成熟期间，以及（5）SARS-COV-2病毒融合中峰值蛋白的构象动力学。 我们的策略是开发多尺度模拟方法，以将一个长度尺度的分子行为联系到 下一个。将开发出粗粒（CG）方法和减少的表示模型，以保留 生物过程的基本物理学，并且在计算上也有效地模拟大型病毒 过程。全原子（AA）模拟将用于准确探测蛋白构象动力学。纽带 裂解和形成将使用混合量子古典方法来描述，例如量子 机械/分子力学（QM/mm）计算。这些模拟将作为 开发基于混合动力学蒙特卡洛分子动力学（MC/MD）的反应性CG模型 量子现象至CG量表。 关于病毒复制的计算预测将与领先 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 分子模拟，病毒学和计算生物物理学。这些研究的发现有可能 有助于制定对抗病毒感染的新治疗策略。