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. We applied this method to a set
of selected receptor targets with their corresponding ligands providing
detailed studies of molecular binding free energy predictions. The
results show that the CHMC gives an excellent accounting of the free
energy surfaces and binding free energies at a reasonable computational
cost.