Theory and SImulation of Viral Replication

病毒复制理论与模拟

• 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
• 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

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.

项目总结