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Principal Investigator: Alvin Yu
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $249,000
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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Acid><Play><Polyproteins><Process><Property><Protease Gene><Proteases><Protein Conformation><Protein Domains><Proteinases><Proteins><Proteolytic Enzymes><Quantum Mechanics><RBCC/TRIM Motif><Receptor Protein><Research><Retroviral Antigen gag Protein><Reverse Transcription><Reverse Transcription Induction><Rhesus Macaque><Rhesus Monkey><Roentgen Rays><Role><Rupture><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 transmission><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Series><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Statistical Data Analyses><Statistical Data Analysis><Statistical Data Interpretation><Structural Biologist><Structure><Surface><System><TRIM Motif><Tertiary Protein Structure><Testing><Time><Transcription Process><Tripartite Motif><United States National Institutes of Health><Viral><Viral Diseases><Viral Genetics><Viral Genome><Viral gag Proteins><Virion><Virus><Virus Diseases><Virus Particle><Virus Replication><Virus-HIV><Work><Wuhan coronavirus><X-Radiation><X-Ray 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