Journal
BIOPHYSICAL JOURNAL
Volume 96, Issue 8, Pages 3065-3073Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2009.01.009
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Funding
- U.S. Department of Energy [DE-FG0206ER46296, DE-AC03-76SF0009]
- National Energy Research Scientific Computing Center (NERSC)
- Directorate For Engineering [852353] Funding Source: National Science Foundation
- Div Of Chem, Bioeng, Env, & Transp Sys [852353] Funding Source: National Science Foundation
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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.
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