An MD View of Ligand Binding

Protein–ligand complexes in crystal structures are well described by an array of bonding interactions among precisely defined functional groups. The present work examines how one representative complex behaves in one-microsecond molecular dynamics simulations, starting from a crystal structure with a native biological ligand bound, and proceeding to simulations of structures derived by docking of that native ligand, and then to docking of selected ligand analogs. The MD behaviors and system energies calculated in RMSD plateau regions using MM/GBSA are similar when initiated from the crystal structure or the structure with the docked native ligand, although independent replicate simulations differ. Despite these similarities, interatomic contact frequencies indicate that some contacts observed in the crystal structure are rarely sampled again; others are sampled only intermittently; and new contacts are recruited that can be more persistent. Docked structures of non-native ligand analogs were chosen for simulation by screening manually for features consistent with known binding interactions, and these displayed behaviors similar to those for the native ligand and, in some cases, similar calculated energies. Overall, ligands appear to cooperate dynamically with the protein in forming the observed interactions.