Hepatitis B virus (HBV) is a major cause of liver disease, including cirrhosis and cancer, for which no cure has been discovered. The HBV capsid, an icosahedral protein shell that encases the viral genome, plays an essential role in HBV infection. The capsid assembles from 120 capsid protein (Cp) homodimers. Drug molecules known as Cp allosteric modulators disrupt capsid assembly in vitro to prevent proper packaging of the genome. Here, all-atom molecular dynamics (MD) simulations of intact, drug-bound capsids are applied to investigate the mechanisms by which two classes of CpAMs (HAPs and PPAs) disrupt capsid structure, dynamics, and assembly. The capsid’s response to drug-induced perturbation, at full and partial CpAM saturation, reveals new details regarding its biophysical properties and biological function. Microsecond simulations of the capsid in its native environment at chemical resolution enable characterization of drug binding modes far beyond what has been achieved through experimentally-determined structures. The results of this study are relevant to the development of new therapeutics that target the capsid of HBV.

Mechanistic insights into the drug-induced disruption of the hepatitis B virus revealed by all-atom molecular dynamics simulations

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.