SMBp Group Meeting: James Gambert (Georgia Tech)

Friday Apr 14, 2023, 1:30 PM → 2:00 PM America/New_York

3rd Floor Classroom/3-Flatiron Institute (162 5th Avenue)

Speaker: James Gumbart , Georgia Tech

 

Topic: Computing our way to a healthier future: How we are using MD simulations to understand the viruses HBV and SARS-CoV-2

 

Abstract: Viruses are a constantly evolving threat that require novel approaches to combat them. This talk will focus on the use of computational tools, especially molecular dynamics (MD) simulations, to understand two important viruses: Hepatitis B Virus (HBV) and SARS-CoV-2. HBV is the leading cause of liver complications, including cirrhosis, hepatocellular carcinoma, and liver failure. Its protein capsid shell is composed of 120 dimers of the core protein, which assemble through multiple intermediate states, most notably tetramers and hexamers; interfering with assembly is a promising approach for developing antiviral agents. Starting from MD simulations of these intermediates with and without bound capsid assembly modifiers (CAMs), we found that distinct conformations, characterized by two angles, are induced depending on whether the bound compound is known to accelerate or misdirect capsid assembly. Thus, we can predict the mechanism of action of CAMs by observing the conformations adopted by intermediates very early in the assembly process, which can also be used to design new ones. For SARS-CoV-2, petascale-class MD simulations and free-energy calculations were used to determine the minimum-free-energy pathway for opening the S-protein trimer, a necessary step for binding to the host cell receptor ACE2. Our simulations revealed, in particular, the role of S-protein glycans in modulating the opening process. These findings demonstrate how computational tools, such as MD simulations, can be used to understand viruses and develop novel antiviral agents, which could have a significant impact on public health.