Electrostatic regulation of genome packaging in human hepatitis B virus.
Hepatitis B virus (HBV) is a contagious human pathogen causing liver diseases such as cirrhosis and hepatocellular carcinoma. An essential step during HBV replication is packaging of a pregenomic (pg) RNA within the capsid of core antigens (HBcAgs) that each contains a flexible C-terminal tail rich in arginine residues. Mutagenesis experiments suggest that pgRNA encapsidation hinges on its strong electrostatic interaction with oppositely charged C-terminal tails of the HBcAgs, and that the net charge of the capsid and C-terminal tails determines the genome size and nucleocapsid stability. Here, we elucidate the biophysical basis for electrostatic regulation of pgRNA packaging in HBV by using a coarse-grained molecular model that explicitly accounts for all nonspecific interactions among key components within the nucleocapsid. We find that for mutants with variant C-terminal length, an optimal genome size minimizes an appropriately defined thermodynamic free energy. The thermodynamic driving force of RNA packaging arises from a combination of electrostatic interactions and molecular excluded-volume effects. The theoretical predictions of the RNA length and nucleocapsid internal structure are in good agreement with available experiments for the wild-type HBV and mutants with truncated HBcAg C-termini.
Jiang
Tao
T
Department of Chemical and Environmental Engineering, University of California, Riverside, California, USA.
Wang
Zhen-Gang
ZG
Wu
Jianzhong
J
D000465:Algorithms; D000595:Amino Acid Sequence; D016679:Genome, Viral; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics* / Q000502:physiology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D019251:Nucleocapsid / Q000737:chemistry / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D055672:Static Electricity; D013816:Thermodynamics; D019065:Virus Assembly / Q000502:physiology*
D006512:Hepatitis B Core Antigens; D012367:RNA, Viral