Ligand docking to proteins undergoing large conformational changes

Abstract

Conformational transitions and ligand binding to the enzyme adenylate kinase were investigated by computational docking. Autodock was used to investigate the dynamics of 92 atomistic conformers, which have been previously obtained by a confor mational sampling algorithm- ClustENM. First the internal geometry of the atomistic ClustENM conformers were validated by the MolProbity server. Four different ligands, namely AP5, ATP, ADP and AMP, were docked on each conformer to determine the favorable docking poses in terms of low energies and ligand RMSD values. Docking of ATP to the side of the LID domain gave the best results among all ligands, which is ac companied by LID closure to various extents. Minimum RMSD is obtained where ATP ligand docked to LID domain with 0.63 ˚A. For multiple conformers, successful poses were found for docking of any ligand to the LID side, whereas dockings to the side of the NMP domain did not yield any successful poses for any of the ligands. Results are mostly in compliance with GOLD procedure especially for the ATP case. To analyze the changes in dynamics for the protein-ATP poses, Dynomics web server was used. Moreover, key protein-ligand interactions were determined by Ligplot, which pointed to the interactions around the phosphate groups of the ligand in the closed crystal struc ture. Intermediate structures with half closed LID were successful for docking of the ligands, indicating a combination of induced fit and conformational search algorithms.