Biological and Medicinal Chemistry

All-atom molecular dynamics study of hepatitis B virus containing pregenome RNA in solution



Immature hepatitis B virus (HBV) captures nucleotides in its capsid for reverse transcription. The nucleotides and nucleotide analogue drugs, which are triphosphorylated and negatively charged in the cell, approach the capsid via diffusion and are absorbed into it. In this study, we performed a long-time molecular dynamics (MD) calculation of the entire HBV capsid containing pregenome RNA to investigate the interactions between the capsid and negatively charged substances. Electric field analysis demonstrated that negatively charged substances can approach the HBV capsid by thermal motion, avoiding spikes. The substances then migrate all over the floor of the HBV capsid. Finally, they find pores through which they can pass through the HBV capsid shell. Free energy profiles were calculated along these pores for small ions to understand their permeability through the pores. Anions (Cl-) showed higher free energy barriers than cations (Na+ and K+) through all pores, and the permeation rate of Cl- was eight times slower than that of K+ or Na+. Furthermore, the ions were more stable in the capsid than in the bulk water. Thus, the HBV capsid exerts ion selectivity for uptake and provides an environment for ions, such as nucleotides and nucleotide analogue drugs, to be stabilized within the capsid.

Version notes

The manuscript was changed from the preprint version to the accepted version.


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Supplementary material

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Supplementary Material
Detailed HBV modeling methods and the supporting figure referred in the text are provided in the supplementary material.