Abstract
Entecavir, triphosphorylated in liver cells, is an antiviral reagent against Hepatitis B virus (HBV). The reagent inhibits reverse transcription of RNA inside the virus capsid. In the present study, free energy profile of an Entecavir triphosphate (ETVTP) molecule has been calculated when it passes through pores of the capsid along two- and three-fold rotational symmetry axes in order to investigate permeation pathway of the reagent to the inside of the capsid. The calculations have been done based on thermodynamic integration (TI) method combined with all-atomistic molecular dynamic (MD) calculations. A free energy minimum of −19 kJ/mol was found at the entrance of the pore from the outside along the three-fold symmetry axis. This stabilization is from the interaction of negatively charged ETVTP with positively charged capsid methionine residues. This excess free energy concentrates of the reagent at the entrance of the pore by a factor of about 2000. A free energy barrier of approximately 13 kJ/mol was also found near the exit of the pore to the inside of the capsid due to narrow space of the pore surrounded by hydrophobic wall made by proline residues and negatively charged wall by aspartic acid residues. There, ETVTP is partially dehydrated in order to pass through the narrow space, which causes the great free energy loss. Further, the negatively charged residues produce repulsive forces on the ETVTP molecule. In contrast, in the case of the pore along the two-fold symmetry axis, the calculated free energy profile showed shallower free energy minimum, −4 kJ/mol at the entrance in spite of the similarly high barrier, 7 kJ/mol, near the exit of the pore.
Article note
A collection of invited papers based on presentations at the 36th International Conference of Solution Chemistry (ICSC-36), held in Xining, China, 4–8 August 2019.
Acknowledgment
We would like to thank Mr. S. Tsurumaki for preparing the figures of this paper. This work was supported by MEXT as “Priority Issue on Post-K computer” (Building Innovative Drug Discovery Infrastructure Through Functional Control of Biomolecular Systems) 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) using computational resources of the K computer provided by the Funder Id: http://dx.doi.org/10.13039/501100006321, RIKEN, Funder Id: http://dx.doi.org/10.13039/501100006264, Center for Computational Science through the HPCI System Research project (Project ID: hp170255 and hp170205, respectively). Calculations were also performed at the Research Center for Computational Science, Okazaki, Japan, at the Information Technology Center of Nagoya University, and at the Institute for Solid State Physics, the University of Tokyo.
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Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/pac-2020-0109).
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