Molecular Models for the Assembly and Replication of Hepatitis B Virus
Hepatitis B virus (HBV) infects more than 2 billion people alive today and is responsible for over 1 million deaths caused by acute and chronic hepatitis and hepatocellular carcinoma every year. Although remarkable progress has been made in recent years, effective treatment and eradication of chronic HBV infection remain as a tremendous therapeutic challenge. Experimental investigations over the past few decades have resulted in vast information on the characteristic features of viral replication and molecular structures of the HBV genome as well as the viral proteins. However, it has long been recognized that the viral replication process is regulated by a balanced interaction of the geometric material and its viral proteins in a crowded cellular milieu that is hardly detectable with direct experimental means. Molecular modeling that provides a quantitative analysis of important intermolecular interactions will be invaluable for unraveling the microscopic details of physicochemical processes underlying viral formation and replication cycle and for designing new experiments to develop novel anti-viral strategies.
This Ph.D. research focuses on molecular modeling of capsid formation, genome packaging and maturation of HBV particles under various mutagenesis and physiological conditions. A suite of theoretical models has been developed to facilitate better understanding of the fundamentals of viral replication cycles and enabling new therapeutic breakthrough for future treatment of HBV infection. Specifically, I applied an effective coarse-grained model for the key viral components and quantified the stability of nucleocapsids based on statistical mechanics. The theoretical model yields faithful results for describing the effects of temperature and ion concentration on viral particle formation, supporting an experimentally derived hypothesis that suggests the balanced electrostatic interaction for the capsid stability and genome encapsidation. In addition, I analyzed the thermodynamic basis for the viral genome packaging, the dynamic structures of nucleocapsids at different stages of the replication cycle, and the correlation between the viral structure to the maturing signals of HBV nucleocapsids by using the classical density functional theory (DFT). The DFT analysis provides a quantitative description of the microscopic structure of the protein-RNA/DNA complex underlying nucleocapsid formation and the related thermodynamic properties. The theoretical predictions on the optimal genome length and nucleocapsid structure are in good agreement with available experiments for the wild type HBV and mutants with truncated C-terminal domain of the capsid proteins. To establish concrete connection between the capsid structure and HBV maturing signals, I further investigated molecular recognition between viral envelope and capsid proteins. Specific protein-protein interactions were identified through molecular docking and molecular dynamic (MD) simulations. It is expected accomplishments from this work will contribute to broadening a fundamental understanding of the HBV replication cycle.