The dynamic States of Hepatitis B virus Capsid Monomers under the Impact of Different Class of Capsid-Assembly Modulators

Hepatitis B virus (HBV) remains a global health challenge. Capsid assembly modulators (CAMs) represent a promising class of antiviral agents that disrupt HBV core protein (HBc) function. Understanding the structural and dynamic impact of CAMs on HBc is crucial for the development of next-generation antiviral therapies. This study employed molecular dynamics (MD) simulations to evaluate the conformational behavior of HBc monomers in unbound and ligand-bound states. Different classes of CAMs—Heteroaryldihydropyrimidine (HAP), Sulfamoylbenzamide (SBA), and Ciclopirox—were analyzed to assess their impact on HBc stability, flexibility, and interaction energy. RMSD analysis revealed that HAP binding stabilized HBc, reducing backbone fluctuations, whereas SBA and PPA increased HBc flexibility. RMSF calculations demonstrated that CAM interactions influenced loop and terminal region dynamics. PCA suggested ligand-specific alterations in HBc’s essential motions, with Sulfamoylbenzamide inducing the highest variance. Salt bridge analysis indicated that Ciclopirox formed the strongest electrostatic interactions, stabilizing its binding. DSSP secondary structure analysis showed that CAMs disrupted α-helical content, with Sulfamoylbenzamide and Ciclopirox exhibiting the most pronounced structural rearrangements. This study provides novel insights into CAM-induced conformational changes in HBc. While HAP stabilizes the core protein, SBA and Ciclopirox increase flexibility, potentially leading to misassembled or destabilized capsids. These findings contribute to the rational design of CAM-based antiviral therapies and highlight key structural determinants for future drug optimization.