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Published April 22, 2009 | public
Journal Article

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.

Additional Information

© 2009 Biophysical Society Published by Elsevier Inc. Submitted August 28, 2008, and accepted for publication January 8, 2009. The authors are grateful to Dr. Jianming Hu for insightful comments on the biological aspects of HBV. For financial support and computer time allocations, we are grateful to the U.S. Department of Energy (DE-FG02- 06ER46296) and to the National Energy Research Scientific Computing Center (NERSC), which is supported by the Office of Science of the U.S. Department of Energy under contract No. DE-AC03-76SF0009.

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