Accounting for Induced-Fit Effects in Docking: What is Possible and What is Not?

Christoph      A. Sotriffer

doi:10.2174/156802611794863544

Abstract

Proteins can undergo a variety of conformational changes upon ligand binding. Although different mechanisms may play a role, the phenomenon is commonly referred to as induced fit to indicate that the tight structural complementarity of the interaction partners is a consequence of the binding event. Docking methods need to take into account this ability of the ligand and the protein to mutually adapt to each other when forming a complex. Handling the ligand as flexible is already common practice in docking applications. This is not yet the case for the protein. In fact, the accurate prediction of protein conformational changes upon ligand binding is still a major challenge, even more if computational speed is an issue, as for example in virtual screening applications. However, significant progress has been made over the past years and many valuable approaches have become available to address the protein flexibility problem and to provide more reliable docking predictions for complexes governed by significant induced-fit effects. This review provides a brief overview of the current situation, the most recent advances, and the remaining limitations of flexible protein docking, with particular focus on approaches handling protein flexibility simultaneously with ligand placement in the docking process.

Keywords: Protein flexibility, conformational changes, induced fit, structure-based drug design, docking, scoring, protein-ligand complexes, ligand binding, NMR, PDB, enzymes, substrate binding, conformational selection, NADPH, cofactor, induced conformational change, 3D structures, RosettaLigand, flexibility, optimization, SLIDE, algorithms, ICM method, FlexX, GOLD, IFD, MRC docking, NMR data, DOCK, AutoDock, MD, FlexE, LMOD, domain, Gibbs free energy, entropic, enthalpic, AR, Leu300, Cys298-Leu300, X-ray crystallography, Trp20, Lys21, aldose reductase, TGT, MCM, ROSETTA, RMSD, SAMPL-1, JNK3, TAMD, MAP, ICM, MRC, EN NMA, SCARE, MADAMM, CHARMM, LGA, FITTED, CYP2D6, SOM, SA, FlexScreen, DUD, ChiFlex, CDOCKER, CDK2