Assembly-active and -inactive forms of HBV capsid protein provide distinctly different binding sites for capsid assembly modulators

In this study, we computationally analyzed published structures of Hepatitis B virus core protein (HBc) bound with different core protein assembly modulators (CAMs) that interfere with HBV assembly. We focused on comparing the difference in CAM binding between two mutations of HBc, one that forms flat sheets, and one that forms icosahedra similar to the wild type virus capsid. We did this by aligning all currently published HBc-CAM structures by their CAM binding pockets. This allowed us to both quantitatively and qualitatively compare the CAM binding pockets of these two different structure types. We find that there are critical differences in the angle of interaction, capsid orientation angle, CAM pocket shapes and sizes, and CAM interacting residues between icosahedral and sheet based HBc structures.