Weighted Ensemble Simulations Reveal Novel Conformations and Modulator Effects in Hepatitis B Virus Capsid Assembly.

Molecular dynamics (MD) simulations provide a detailed description of biophysical processes, allowing mechanistic questions to be addressed at the atomic level. The promise of such approaches is partly hampered by well-known sampling issues of typical simulations, where time scales available are significantly shorter than the process of interest. For the process of interest here, the binding of modulators of Hepatitis B virus capsid self-assembly, the binding site is at a flexible protein-protein interface. Characterization of the conformational landscape and how it is altered upon ligand binding is thus a prerequisite for a complete mechanistic description of capsid assembly modulation. However, such a description can be difficult due to the aforementioned sampling issues of standard MD, and enhanced sampling strategies are required. Here, we employ the weighted ensemble methodology to characterize the free-energy landscape of our earlier determined functionally relevant progress coordinates. It is shown that this approach provides conformations outside those sampled by standard MD, as well as an increased number of structures with correspondingly enlarged binding pockets conducive to ligand binding, illustrating the utility of weighted ensemble for computational drug development.