PT  - JOURNAL ARTICLE
AU  - Farzaneh Mohajerani
AU  - Botond Tyukodi
AU  - Christopher J. Schlicksup
AU  - Jodi A. Hadden-Perilla
AU  - Adam Zlotnick
AU  - Michael F. Hagan
TI  - Multiscale Modeling of Hepatitis B Virus Capsid Assembly and its Dimorphism
AID  - 10.1101/2022.02.23.481637
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.02.23.481637
4099  - http://biorxiv.org/content/early/2022/02/23/2022.02.23.481637.short
4100  - http://biorxiv.org/content/early/2022/02/23/2022.02.23.481637.full
AB  - Hepatitis B Virus (HBV) is an endemic, chronic virus that leads to 800,000 deaths per year. Central to the HBV lifecycle, the viral core has a protein capsid assembled from many copies of a single protein. The capsid protein adopts different (quasi-equivalent) conformations to form icosahedral capsids containing 180 or 240 proteins, T=3 or T=4 respectively in Caspar-Klug nomenclature. HBV capsid assembly has become an important target for new antivirals; nonetheless the assembly pathways and mechanisms that control HBV dimorphism remain unclear. We describe computer simulations of HBV assembly, using a coarse-grained model that has parameters learned from all-atom molecular dynamics simulations of a complete HBV capsid, and yet is computationally tractable. Dynamical simulations with the resulting model reproduce experimental observations of HBV assembly pathways and products. By constructing Markov state models and employing transition path theory, we identify pathways leading to T=3, T=4, and other experimentally observed capsid morphologies. The analysis identifies factors that control this polymorphism, in particular, the conformational free energy landscape of the capsid proteins and their interactions.Competing Interest StatementThe authors have declared no competing interest.