Computational modeling to explain Hepatitis-B Virus capsid assembly, dimorphism, and disruption by antiviral drugs

Assembly of the outer protein shell (capsid) of a virus is an essential step in its lifecycle. Understanding the mechanisms underlying assembly and the factors that determine the final morphology will guide development of antiviral drugs that disrupt or redirect assembly processes. Hepatitis-B Virus (HBV) assembles from a single capsid protein, which adopts different conformations to form icosahedral capsids with different sizes containing 180 or 240 proteins, T=3 or T=4 respectively in the Caspar-Klug nomenclature. Despite intensive experimental and theoretical investigation, the assembly pathways and mechanisms that control HBV dimorphism remain unclear.
In this talk we will describe dynamical computer simulations of HBV assembly, using a model which is minimal and highly computationally tractable, but has parameters learned from atomistic simulation data of whole HBV capsids. The simulation results identify pathways leading to T=3 and T=4 capsid morphologies, and suggest key factors which control this dimorphism. We describe tests of the model against experimental data, and propose mechanisms of action for antiviral drugs that result in assembly of malformed shells in recent HBV experiments.