Sensitivity of an empirical affinity scoring function to changes in receptor-ligand complex conformations

A combination of empirical scoring and conformational sampling for ligand binding affinity prediction is examined. The behaviour of a scoring function with respect to the sensitivity to conformational changes is investigated using ensembles of structures generated by molecular dynamics simulation. The correlation between the calculated score and the coordinate deviation from the experimental structure is clear for the complex of arabinose with arabinose-binding protein, which is dominated by hydrogen bond interactions, while the score calculated for the hydrophobic complex between retinol and retinol binding protein is rather insensitive to ligand conformational changes. For typical ensembles of structures generated by molecular dynamics at 300 K, the variation of the calculated score is considerably smaller than that of the underlying molecular mechanics interaction energies.