BioE PhD Defense Presentation- Zixing Fan

Advisor:  

James C. Gumbart, Ph.D. (School of Physics, Georgia Institute of Technology)  

Committee:  

M. G. Finn, Ph.D. (School of Chemistry and Biochemistry, Georgia Institute of Technology)

Peter Kasson, Ph.D. (School of Chemistry and Biochemistry; Coulter Department of Biomedical Engineering, Georgia Institute of Technology)

Jeffrey Skolnick, Ph.D. (School of Biological Sciences, Georgia Institute of Technology)

Adegboyega Oyelere, Ph.D. (School of Chemistry and Biochemistry, Georgia Institute of Technology)

Modulating Hepatitis B Virus Capsid Assembly and Function through Pharmacological Intervention  

Hepatitis B virus (HBV) is a major global health burden that causes chronic liver disease. Its replication depends on the assembly of a protein capsid, making this process an important target for antiviral intervention. This work integrates molecular dynamics simulations and biophysical experiments to investigate how small molecules interact with and modulate the HBV core protein across different structural contexts. First, biophysics-guided approaches were used to identify ligands targeting the inter-dimer assembly interface, showing that small molecules can perturb capsid assembly through changes in inter-subunit interactions. Second, free-energy calculations were conducted to characterize the conformational landscape of a key assembly intermediate, providing insight into structural features that may influence assembly nucleation. Third, a distinct intra-dimer pocket was characterized using fragment-based mapping and pharmacophore modeling, enabling virtual screening and experimental validation of ligands with extended binding modes. Together, these results provide a framework for understanding how small molecules can modulate HBV capsid behavior and highlight new directions for antiviral design.