Jiang Tao, Wang Zhen-Gang, Wu Jianzhong
Department of Chemical and Environmental Engineering, University of California, Riverside, California, USA.
Biophys J. 2009 Apr 22;96(8):3065-73. doi: 10.1016/j.bpj.2009.01.009.
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.
乙型肝炎病毒（HBV）是一种具有传染性的人类病原体，可引发肝硬化和肝细胞癌等肝脏疾病。HBV复制过程中的一个关键步骤是将前基因组（pg）RNA包装到核心抗原（HBcAg）的衣壳内，每个核心抗原都含有一个富含精氨酸残基的柔性C末端尾巴。诱变实验表明，pgRNA衣壳化取决于其与HBcAg带相反电荷的C末端尾巴的强静电相互作用，并且衣壳和C末端尾巴的净电荷决定了基因组大小和核衣壳稳定性。在此，我们通过使用一种粗粒度分子模型来阐明HBV中pgRNA包装静电调节的生物物理基础，该模型明确考虑了核衣壳内关键成分之间的所有非特异性相互作用。我们发现，对于具有可变C末端长度的突变体，最佳基因组大小可使适当定义的热力学自由能最小化。RNA包装的热力学驱动力来自静电相互作用和分子排除体积效应的组合。RNA长度和核衣壳内部结构的理论预测与野生型HBV和具有截短HBcAg C末端的突变体的现有实验结果高度一致。
