Computational modeling of virus assembly in the presence of biomolecular condensates and antiviral agents

The assembly of a virus capsid (outer protein shell) is an essential step in its lifecycle. Understanding the assembly pathways and factors that enable robust assembly will fundamentally advance virology and contribute to new antiviral treatments that disrupt assembly. However, simulating self-assembly is challenging because relevant links and timescales are orders of magnitude larger than the components. I will describe computational models that bridge these timescales, and their application to two aspects of virus assembly.



(1) Hepatitis-B Virus (HBV) assembles icosahedral capsids with different sizes containing 180 or 240 proteins and T=3 or T=4 symmetries, respectively. The assembly pathways and mechanisms that control this dimorphism remain unclear. We have developed a framework for tractable computational models capable of simulating assembly timescales, by learning model parameters directly from atomistic simulations. Applying this framework to HBV identifies pathways leading to T=3 and T=4 capsid morphologies and key factors that control this dimorphism as well as long-lived overgrown intermediates that were recently observed in experiments. We then describe how small-molecule antiviral agents can alter these assembly pathways to disrupt formation of infectious virions.



(2) Many viruses construct biomolecular condensates (often known as liquid-liquid phase separation) within their host cells, and assemble the capsid and/or package the genomic nucleic acid within those condensates. However, how the condensate facilitates assembly or packaging remains unclear. Using theoretical and computational models, we show that coupling between self-assembly and condensate formation can accelerate assembly and enhance robustness against parameter variations by orders of magnitude. Furthermore, condensate-coupled assembly can proceed by multiple pathways, including assembly of the capsids within the condensate interior or adsorption of the proteins at the interface followed by assembly into capsids.