Theory and SImulation of Viral Replication

病毒复制理论与模拟

基本信息

批准号：
10349805
负责人：
Alvin Yu
金额：
$ 9万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349805
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 Crystallization 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 Mechanics Methodology Methods Modeling Molecular Molecular Conformation Morphology Nucleotides Organism Pattern Peptide Hydrolases Peptides Phase Physics Phytic Acid Play Polyproteins Process Property Protein Conformation Proteins Research Reverse Transcription 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 base 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

项目摘要

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.

项目概要病毒是在生物体活细胞内复制的感染因子，它对于生物体的活细胞内复制仍然至关重要。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操作从原子尺度现象的物理和化学过程，例如量子化学键断裂到大规模过程，例如蛋白质自组装，这些过程从根本上来说都是如此。多尺度，因为它们跨越从分子到介观的时间和长度尺度。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随后重新组装成富勒烯衣壳的结构域蛋白 (CA) 我们的首要目标是研究。使用理论、基于物理的建模和计算机来研究病毒复制中涉及的分子过程模拟。该提案重点关注病毒生命周期的五个关键方面：（1）先天免疫传感器如何像含有蛋白 5 α (TRIM5α) 的三联基序通过组装成六边形图案来限制病毒感染晶格以物理方式笼罩病毒核心并向衣壳发出降解信号，（2）材料和物理包裹和保护病毒基因组的衣壳的特性，(3) pH-的化学特征门控孔分布在整个衣壳表面，（4）发生大规模的形态变化病毒体成熟过程中的变化，以及 (5) SARS-CoV-2 病毒体融合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，将某一长度尺度的分子行为与接下来将开发保留的粗粒度（CG）方法和简化表示模型。生物过程的基本物理原理，并且计算效率也高，可以模拟大规模病毒全原子（AA）模拟将用于精确探测蛋白质构象动力学。将使用混合量子经典方法来描述裂解和形成，例如量子这些模拟将作为机械/分子力学（QM/MM）计算的基础。开发基于混合动力学蒙特卡罗分子动力学 (MC/MD) 的反应 CG 模型以链接 CG 尺度的量子现象。关于病毒复制的计算预测将与领先的公司合作进行测试和验证总的来说，这些研究的见解将广泛影响结构生物学家和生物化学家的领域。这些研究的结果有可能促进分子模拟、病毒学和计算生物物理学的发展。帮助开发新的治疗策略来对抗病毒感染。