TY - JOUR
T1 - Identification of Factors Promoting HBV Capsid Self-Assembly by Assembly-Promoting Antivirals
AU - Rath, Soumya Lipsa
AU - Liu, Huihui
AU - Okazaki, Susumu
AU - Shinoda, Wataru
N1 - Funding Information:
We thank Profs. Yasuto Tanaka and Katsumi Omagari and Drs. Xibing He and Kota Kasahara for their useful suggestions. This research was supported by MEXT as “Priority Issue on Post-K Computer” (Building Innovative Drug Discovery Infrastructure through Functional Control of Biomolecular Systems). This research used computational resources of the K computer provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research Project (Projects hp150269, hp160223, and hp170255) and supercomputers at Nagoya University.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/2/26
Y1 - 2018/2/26
N2 - Around 270 million individuals currently live with hepatitis B virus (HBV) infection. Heteroaryldihydropyrimidines (HAPs) are a family of antivirals that target the HBV capsid protein and induce aberrant self-assembly. The capsids formed resemble the native capsid structure but are unable to propagate the virus progeny because of a lack of RNA/DNA. Under normal conditions, self-assembly is initiated by the viral genome. The mode of action of HAPs, however, remains largely unknown. In this work, using molecular dynamics simulations, we attempted to understand the action of HAP by comparing the dynamics of capsid proteins with and without HAPs. We found that the inhibitor is more stable in higher oligomers. It retains its stability in the hexamer throughout 1 μs of simulation. Our results also show that the inhibitor might help in stabilizing the C-terminus, the HBc 149-183 arginine-rich domain of the capsid protein. The C-termini of dimers interact with each other, assisted by the HAP inhibitor. During capsid assembly, the termini are supposed to directly interact with the viral genome, thereby suggesting that the viral genome might work in a similar way to stabilize the capsid protein. Our results may help in understanding the underlying molecular mechanism of HBV capsid self-assembly, which should be crucial for exploring new drug targets and structure-based drug design.
AB - Around 270 million individuals currently live with hepatitis B virus (HBV) infection. Heteroaryldihydropyrimidines (HAPs) are a family of antivirals that target the HBV capsid protein and induce aberrant self-assembly. The capsids formed resemble the native capsid structure but are unable to propagate the virus progeny because of a lack of RNA/DNA. Under normal conditions, self-assembly is initiated by the viral genome. The mode of action of HAPs, however, remains largely unknown. In this work, using molecular dynamics simulations, we attempted to understand the action of HAP by comparing the dynamics of capsid proteins with and without HAPs. We found that the inhibitor is more stable in higher oligomers. It retains its stability in the hexamer throughout 1 μs of simulation. Our results also show that the inhibitor might help in stabilizing the C-terminus, the HBc 149-183 arginine-rich domain of the capsid protein. The C-termini of dimers interact with each other, assisted by the HAP inhibitor. During capsid assembly, the termini are supposed to directly interact with the viral genome, thereby suggesting that the viral genome might work in a similar way to stabilize the capsid protein. Our results may help in understanding the underlying molecular mechanism of HBV capsid self-assembly, which should be crucial for exploring new drug targets and structure-based drug design.
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U2 - 10.1021/acs.jcim.7b00471
DO - 10.1021/acs.jcim.7b00471
M3 - Article
C2 - 29309148
AN - SCOPUS:85042715308
SN - 1549-9596
VL - 58
SP - 328
EP - 337
JO - Journal of Chemical Documentation
JF - Journal of Chemical Documentation
IS - 2
ER -
