TY - JOUR
T1 - All-atom molecular dynamics study of hepatitis B virus containing pregenome RNA in solution
AU - Fujimoto, Kazushi
AU - Yamaguchi, Youhei
AU - Urano, Ryo
AU - Shinoda, Wataru
AU - Ishikawa, Tetsuya
AU - Omagari, Katsumi
AU - Tanaka, Yasuhito
AU - Nakagawa, Atsushi
AU - Okazaki, Susumu
N1 - Funding Information:
We would like to thank Professor Adam Zlotnic for his helpful discussions. We also thank Dr. Hajime Imai for his collaboration during the early stages of this project and Mr. Shuhei Tsurumaki for his help with data processing. This work was supported by MEXT as “Priority Issue on Post-K computer” (Building Innovative Drug Discovery Infrastructure Through Functional Control of Biomolecular Systems) (Project IDs. hp150269, hp160223, hp170255, hp180191, and hp190171) and “General Issue on Post-K computer” (Absorption Mechanism of Inhibitor into Capsid by using All-Atom Molecular Dynamics of Hepatitis B Virus in Solution) (Project IDs. hp160143, hp170205, hp180131, and hp190129) using computational resources of the K computer provided by the RIKEN Center for Computational Science through the HPCI System Research project. This work was also partially supported by MEXT as the “Program for Promoting Research on the Supercomputer Fugaku” (Biomolecular dynamics and function in a living cell using atomistic and coarse-grained simulations) (Project IDs. hp200135 and hp210177). Calculations were also performed by supercomputers at the Research Center for Computational Science, Okazaki, Japan, at the Information Technology Center of Nagoya University, at the Information Initiative Center, Hokkaido University, at the Cybermedia Center, Osaka University, and at the Institute for Solid State Physics, the University of Tokyo.
Publisher Copyright:
© 2021 Author(s).
PY - 2021/10/14
Y1 - 2021/10/14
N2 - Immature hepatitis B virus (HBV) captures nucleotides in its capsid for reverse transcription. The nucleotides and nucleotide analog 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 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 analog drugs, to be stabilized within the capsid.
AB - Immature hepatitis B virus (HBV) captures nucleotides in its capsid for reverse transcription. The nucleotides and nucleotide analog 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 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 analog drugs, to be stabilized within the capsid.
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U2 - 10.1063/5.0065765
DO - 10.1063/5.0065765
M3 - Article
C2 - 34654297
AN - SCOPUS:85116877756
SN - 0021-9606
VL - 155
JO - Journal of Chemical Physics
JF - Journal of Chemical Physics
IS - 14
M1 - 145101
ER -
