PNNL

Abstract

Even if the structure of a receptor has been determined experimentally, it may not be a conformation to which a ligand would bind when induced fit effects are significant. Here we evaluate the use of an ensemble of receptor conformations generated from a molecular dynamics simulation for molecular docking. Two molecular dynamics simulations were carried out to generate snapshots for protein kinase A (PKA): one with the ligand bound, the other without. The ligand, balanol, was then docked to conformations of the receptors presented by these trajectories. The Larmarkian genetic algorithm in Autodock1,2 was used in the docking. Three ligand models were used: rigid, flexible, and flexible with torsional potentials. When the snapshots were taken from the molecular dynamics simulation of the protein-ligand complex, the correct docking structure was found in all cases. On the other hand, when the snapshots were taken from the apo simulation, several clusters of structures were found. Out of the ten docking runs for each snapshot, at least one structure was close to the correctly docked structure when the flexible ligand models were used. However, the lowest energy structures, according to Autodock1,2, did not always correspond to the correctly docked structure. Rescoring using a more sophisticated Generalized Born electrostatics model did not improve the identification of the correctly docked structure. On the other hand, the correctly docked structure appeared more frequently as the lowest energy structures with the Autodock1,2 scoring function. This can provide a useful criterion for selecting the correctly docked structure from clusters of structures obtained from molecular docking experiments.