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ROSETTALIGAND: Protein–small molecule docking with full side‐chain flexibility
Author(s) -
Meiler Jens,
Baker David
Publication year - 2006
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21086
Subject(s) - searching the conformational space for docking , docking (animal) , van der waals force , solvation , protein–ligand docking , molecule , side chain , small molecule , chemistry , energy minimization , monte carlo method , computational chemistry , protein structure , force field (fiction) , binding energy , ramachandran plot , hydrogen bond , macromolecular docking , macromolecule , molecular dynamics , physics , virtual screening , computer science , atomic physics , mathematics , artificial intelligence , polymer , medicine , biochemistry , statistics , nursing , organic chemistry
Protein–small molecule docking algorithms provide a means to model the structure of protein–small molecule complexes in structural detail and play an important role in drug development. In recent years the necessity of simulating protein side‐chain flexibility for an accurate prediction of the protein–small molecule interfaces has become apparent, and an increasing number of docking algorithms probe different approaches to include protein flexibility. Here we describe a new method for docking small molecules into protein binding sites employing a Monte Carlo minimization procedure in which the rigid body position and orientation of the small molecule and the protein side‐chain conformations are optimized simultaneously. The energy function comprises van der Waals (VDW) interactions, an implicit solvation model, an explicit orientation hydrogen bonding potential, and an electrostatics model. In an evaluation of the scoring function the computed energy correlated with experimental small molecule binding energy with a correlation coefficient of 0.63 across a diverse set of 229 protein– small molecule complexes. The docking method produced lowest energy models with a root mean square deviation (RMSD) smaller than 2 Å in 71 out of 100 protein–small molecule crystal structure complexes (self‐docking). In cross‐docking calculations in which both protein side‐chain and small molecule internal degrees of freedom were varied the lowest energy predictions had RMSDs less than 2 Å in 14 of 20 test cases. Proteins 2006. © 2006 Wiley‐Liss, Inc.