Receptor-Ligand Binding Free Energies from a Consecutive Histograms Monte Carlo Sampling Method.

To obtain accurate and converged free energy calculations for ligand binding to biomolecular systems requires validated force fields and extensive sampling of the energy landscape, which requires exhaustive and effective conformational searching methods. Herein, we introduce the consecutive histograms Monte Carlo (CHMC) sampling protocol that generates receptor-ligand binding modes within a series of continuously distributed sampling units ranging from placement near the geometric center of the receptor's binding site to fully unbound states. This protocol employs independent energy-state sampling for calculating the ensemble energy within every predefined location along the receptor-ligand dissociation pathway, without the need to traverse the energy barriers as in molecular dynamic simulations during the dissociation procedure.

MovableType Software for Fast Free Energy-Based Virtual Screening: Protocol Development, Deployment, Validation, and Assessment.

For decades, the complicated energy surfaces found in macromolecular protein:ligand structures, which require large amounts of computational time and resources for energy state sampling, have been an inherent obstacle to fast, routine free energy estimation in industrial drug discovery efforts. Beginning in 2013, the Merz research group addressed this cost with the introduction of a novel sampling methodology termed "Movable Type" (MT). Using numerical integration methods, the MT method reduces the computational expense for energy state sampling by independently calculating each atomic partition function from an initial molecular conformation in order to estimate the molecular free energy using ensembles of the atomic partition functions.