FlexE: Efficient molecular docking considering protein structure variations

Side-chain or even backbone adjustments upon docking of different ligands t o the same protein structure, a phenomenon known as induced fit, are freque ntly observed. Sometimes point mutations within the active site influence t he ligand binding of proteins. Furthermore, for homology derived protein st ructures there are often ambiguities in side-chain placement and uncertaint ies in loop modeling which may be critical for docking applications. Nevert heless, only very few molecular docking approaches have taken into account such variations in protein structures. We present the new software tool FlexE which addresses the problem of prote in structure variations during docking calculations. FlexE can dock flexibl e ligands into an ensemble of protein structures which represents the flexi bility, point mutations, or alternative models of a protein. The FlexE appr oach is based on a united protein description generated from the superimpos ed structures of the ensemble. For varying parts of the protein, discrete a lternative conformations are explicitly taken into account, which can be co mbinatorially joined to create new valid protein structures. FlexE was evaluated using ten protein structure ensembles containing 105 cr ystal structures from the PDB and one modeled structure with 60 ligands in total. For 50 ligands (83%) FlexE finds a placement with an RMSD to the cry stal structure below 2.0 Angstrom. In all cases our results are of similar quality to the best solution obtained by sequentially docking the ligands i nto all protein structures (cross docking). In most cases the computing tim e is significantly lower than the accumulated run times for the single stru ctures. FlexE takes about five and a half minutes on average for placing on e ligand into the united protein description on a common workstation. The example of the aldose reductase demonstrates the necessity of consideri ng protein structure variations for docking calculations. We docked three p otent inhibitors into four protein structures with substantial conformation al changes within the active site. Using only one rigid protein structure f or screening would have missed potential inhibitors whereas all inhibitors can be docked taking all protein structures into account. (C) 2001 Academic Press.