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Enhanced docking with the mining minima optimizer: Acceleration and side‐chain flexibility
Author(s) -
Kairys Visvaldas,
Gilson Michael K.
Publication year - 2002
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.10168
Subject(s) - maxima and minima , docking (animal) , ligand (biochemistry) , side chain , computer science , protein–ligand docking , searching the conformational space for docking , algorithm , chemistry , biological system , computational chemistry , virtual screening , molecular dynamics , binding site , mathematics , receptor , biology , medicine , mathematical analysis , biochemistry , nursing , organic chemistry , polymer
The ligand–protein docking algorithm based on the Mining Minima method has been substantially enhanced. First, the basic algorithm is accelerated by: (1) adaptively determining the extent of each energy well to help avoid previously discovered energy minima; (2) biasing the search away from ligand positions at the surface of the receptor to prevent the ligand from staying at the surface when large sampling regions are used; (3) quickly testing multiple different ligand positions and orientations for each ligand conformation; and (4) tuning the source code to increase computational efficiency. These changes markedly shorten the time needed to discover an accurate result, especially when large sampling regions are used. The algorithm now also allows user‐selected receptor sidechains to be treated as mobile during the docking procedure. The energies associated with the mobile side chains are computed as if they belonged to the ligand, except that atoms at the boundary between side chains and the rigid backbone are treated specially. This new capability is tested for several well‐known ligand/protein systems, and preliminary application to an enzyme whose substrate is unknown—the recently solved hypothetical protein YecO (HI0319) from Haemophilus influenzae —indicates that side‐chains relaxations allow candidate substrates of various sizes to be accommodated. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 1656–1670, 2002