Abstract
Hepatitis B Virus causes an epidemic: about 254 million people live with chronic HBV infection, which affects liver function. The viral capsid plays a central role in the HBV lifecycle and appears at nearly every step. Disrupting capsid assembly holds promise as an antiviral strategy, and Core-protein Allosteric Modulators (CAMs) are one class of potential anti-viral agents that do so.
Experiments and all-atom simulations have provided detailed structural information on HBV assembly, including assembly product size distributions, high-resolution cryoEM images of assembly products, and atomic-level capsid dynamics. However, they cannot capture assembly kinetics fully or explain the thermodynamic and kinetic drivers of assembly. Coarse-grained simulations address this gap.
In this dissertation, we investigate HBV capsid assembly using two complementary coarse-grained approaches. First, Monte Carlo simulations of an elastic network reveal how early intermediates dictate assembly pathways and how CAMs alter them. We find that T=4-like structures form preferentially through intermediates with five-fold symmetry, while sheet-like structures emerge from early triangular sheets. Second, using residue-based coarse-graining and Weighted Ensemble (WE) simulations, we elucidate the mechanistic pathway of early intermediate formation. We discover that the fraction of native contacts at dimer interfaces dictates dimer orientation and is a key measure of dimer-dimer binding. We also show how oligomers evolve toward capsids and how constraints from neighboring subunits regulate binding and dihedral angles.
Together, our work reveals that early intermediates are not merely precursors but active determinants of final assembly products. These insights have implications for designing CAMs that target early intermediates not only for HBV but also for other icosahedral viruses.