Predicting the Hepatitis B Virus Capsid Disassembly Process Through Computational Modeling

Martin Gruebele, University of Illinois at Urbana-Champaign

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Martin Gruebele, Po-Chao Wen, Noah Trebesch, Sepehr Dehghanighahnaviyeh, Aaron Chan, Ali Rasouli, Hyun Park, Zhaleh Ghaemi

Despite extensive knowledge from several decades of research on the life cycle of Hepatitis B virus (HBV), chronic
infection by HBV remains an unsolved medical challenge. As a related issue, the mode of action of successful HBV
drugs remain unclear. This knowledge gap may be ameliorated by elucidating the details of interactions between the
virus and the host cell as well as the drugs and virus components. Given the availability of structural models for parts of
the virus, it is now feasible to tackle these issues by constructing and simulating atomistic models of the virus that can
be used to investigate specific steps in the viral infection process. One of the crucial steps during the virus infection
cycle is the disassembly of the virus capsid which leads to the release of the viral DNA into the nucleus. Using a
combination of computational and experimental approaches, we intend to identify the breaking hotspots during the
virus disassembly process. Specifically, we will construct an atomistic model of the entire virus capsid and perform
two sets of simulations, one to predict mechanism for virus capsid disassembly and another to verify the predicted
mechanism. The results of these simulations will be compared to our experimental data. The large size of the solvated
HBV capsid (5.5 million atoms) and the required microsecond time scale, necessitate the use of supercomputing
resources such as Blue Waters. The synergistic combination of our computational approach with experiments will
provide us with a more comprehensive picture of the underlying molecular events that might guide the design of more
effective drugs and shed light on the modes of action of similar viruses.