Equilibrium and Nonequilibrium Ensemble Methods for Accurate, Precise and Reproducible Absolute Binding Free Energy...

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Free energy calculations for protein-ligand complexes are crucial in drug discovery.
• Ensemble methods enhance prediction accuracy, precision, and reproducibility.
• Absolute binding free energy (ABFE) predictions using alchemical methods have been challenging for routine application.

Purpose of the Study:

• To apply ensemble alchemical ABFE methods to a large dataset of 219 ligand-protein complexes.
• To compare the performance of equilibrium and nonequilibrium methods for large-scale ABFE predictions.
• To provide a critical assessment of these methods and recommend an optimal protocol.

Main Methods:

• Ensemble alchemical absolute binding free energy (ABFE) calculations.
• Application to a dataset of 219 protein-ligand complexes.
• Comparison of equilibrium and nonequilibrium alchemical methods.

Main Results:

• Statistically robust ABFE predictions with high accuracy (<1 kcal/mol) were obtained.
• The equilibrium method demonstrated superior accuracy, precision, speed, and cost-effectiveness compared to the nonequilibrium method.
• Free energy distributions were found to be non-normal, with implications for analysis.

Conclusions:

• Ensemble alchemical ABFE methods, particularly the equilibrium approach, are suitable for large-scale drug discovery applications.
• A definitive protocol for optimal ABFE calculations is recommended.
• Exascale computing enables thousands of ABFE calculations within hours using the proposed protocol.