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

Area of Science:

• Biophysics
• Computational Chemistry
• Drug Discovery

Background:

• Molecular dynamics (MD) simulations offer atomic-level insights into biophysical processes.
• Standard MD simulations often suffer from insufficient sampling of relevant timescales.
• Hepatitis B virus (HBV) capsid assembly modulation involves binding at a flexible protein-protein interface, requiring detailed conformational analysis.

Purpose of the Study:

• To address sampling limitations in MD simulations for HBV capsid assembly.
• To characterize the free-energy landscape of HBV capsid assembly modulators.
• To explore the conformational landscape and its alteration upon ligand binding.

Main Methods:

• Employed the weighted ensemble (WE) methodology.
• Utilized WE to characterize the free-energy landscape.
• Analyzed functionally relevant progress coordinates.

Main Results:

• WE simulations provided conformations beyond those sampled by standard MD.
• Observed an increased number of structures with enlarged binding pockets.
• Demonstrated enhanced sampling of the conformational landscape.

Conclusions:

• Weighted ensemble is a powerful tool for overcoming MD sampling issues.
• This approach facilitates the mechanistic description of capsid assembly modulation.
• WE enhances computational drug development for HBV therapeutics.