Free energy calculations offer insights into the influence of receptor flexibility on ligand–receptor binding affinities

• Published in: Journal of computer-aided molecular design Vol. 25; no. 8; pp. 709 - 716
• Main Authors: Dolenc, Jožica, Riniker, Sereina, Gaspari, Roberto, Daura, Xavier, van Gunsteren, Wilfred F.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.08.2011; Springer Nature B.V
• Subjects: Algorithms; alpha-Cyclodextrins - chemistry; Animal Anatomy; Binding Sites; Bromobenzenes - chemistry; CAD; Chemistry; Chemistry and Materials Science; Chlorobenzene; Chlorobenzenes - chemistry; Computer aided design; Computer Applications in Chemistry; Computer Simulation; Deoxyribonucleic acid; Distamycins - chemistry; DNA; DNA - chemistry; DNA - metabolism; Drug Design; Entropy; Histology; Ligands; Molecular biology; Molecular Conformation; Molecular Dynamics Simulation; Morphology; Netropsin - chemistry; Pharmaceutical sciences; Physical Chemistry; Pliability; Toluene; Toluene - chemistry; α-Cyclodextrin; Molecular dynamics; Drug design; Conformational flexibility; DNA–ligand binding
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-011-9453-x

Docking algorithms for computer-aided drug discovery and design often ignore or restrain the flexibility of the receptor, which may lead to a loss of accuracy of the relative free enthalpies of binding. In order to evaluate the contribution of receptor flexibility to relative binding free enthalpies, two host–guest systems have been examined: inclusion complexes of α-cyclodextrin (αCD) with 1-chlorobenzene (ClBn), 1-bromobenzene (BrBn) and toluene (MeBn), and complexes of DNA with the minor-groove binding ligands netropsin (Net) and distamycin (Dist). Molecular dynamics simulations and free energy calculations reveal that restraining of the flexibility of the receptor can have a significant influence on the estimated relative ligand–receptor binding affinities as well as on the predicted structures of the biomolecular complexes. The influence is particularly pronounced in the case of flexible receptors such as DNA, where a 50% contribution of DNA flexibility towards the relative ligand–DNA binding affinities is observed. The differences in the free enthalpy of binding do not arise only from the changes in ligand–DNA interactions but also from changes in ligand–solvent interactions as well as from the loss of DNA configurational entropy upon restraining.