Efficient docking of peptides to proteins without prior knowledge of the binding site

Abstract

Reliability in docking of ligand molecules to proteins or other targets is an important challenge for molecular modeling. Applications of the docking technique include not only prediction of the binding mode of novel drugs, but also other problems like the study of protein-protein interactions. Here we present a study on the reliability of the results obtained with the popular AutoDock program. We have performed systematical studies to test the ability of AutoDock to reproduce eight different protein/ligand complexes for which the structure was known, without prior knowledge of the binding site. More specifically, we look at factors influencing the accuracy of the final structure, such as the number of torsional degrees of freedom in the ligand. We conclude that the Autodock program package is able to select the correct complexes based on the energy without prior knowledge of the binding site. We named this application blind docking, as the docking algorithm is not able to "see" the binding site but can still find it. The success of blind docking represents an important finding in the era of structural genomics.

Toward prediction of functional protein pockets using blind docking and pocket search algorithms

“…In the first group, there are L 1 -complexes with 1dy4, 1e7a, 1eqg, and 1ngp. In these cases, the present AutoDock4 ranking of the correct pose improved to the 1st rank compared with our previous studies 7,8 with AutoDock3, where they had not been found in the best rank. For example, the primary L 1a pocket of propofol on 1e7a had been identified 7 as Rank 2, whereas now it is located in Rank 1 [ Fig.…”

“…2). In four BD-failed cases (1dy4, 1e7a, 1eqg, 1ngp), the crystallographic position of L 1 was identified correctly using the holo targets as Rank 1 in this study, whereas in the earlier papers 7,8 using AutoDock3 these complexes were listed in higher ranks. This improvement may be due to the modified solvation term 19 of the scoring function (Table I) of AutoDock4.…”

“…For the apo target forms, BD generated a top 1 rank only for 1ngp, whereas for 1eqg and 1dy4 only Rank 4 was produced. The above-mentioned second group includes six targets (1hz4, 1ivb, 1ju4, 1lna, 1pth, 3pcn), where AutoDock4 could not improve the ranking/RMSD precision for L 1 on the holo target forms compared with previous studies 7,8 and failed. EADock SF found the correct pose in only one of six cases (1ivb) as Rank 1.…”

“…The blind docking (BD) method has been introduced 7,8 as an extension of the use of the very powerful docking engine AutoDock 9,10 for the abovementioned case 1 where the chemical identity of the ligand is known. During BD, the entire surface of the protein target is scanned for putative binding pockets of the ligand, and an atomic resolution complex structure is resulted.…”

“…During BD, the entire surface of the protein target is scanned for putative binding pockets of the ligand, and an atomic resolution complex structure is resulted. It was shown 7,8 that in many cases, the primary, functional binding pocket of the ligand can be selected from among the identified pockets according to the binding free energy (DG) values corresponding to the interactions of the ligand with the different pockets. Notably, DG is produced on-the-fly by a scoring function during the docking procedure.…”