title: Free energy calculations offer insights into the influence of receptor flexibility on ligand-receptor binding affinities.
abstract: 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.
authors: Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, Zurich, Switzerland.
authors: Jožica
authors: J
authors: Dolenc
authors: Sereina
authors: S
authors: Riniker
authors: Roberto
authors: R
authors: Gaspari
authors: Xavier
authors: X
authors: Daura
authors: Wilfred F
authors: WF
authors: van Gunsteren
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D001969:Bromobenzenes / Q000737:chemistry; D002722:Chlorobenzenes / Q000737:chemistry; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004214:Distamycins / Q000737:chemistry; D015195:Drug Design; D019277:Entropy; D008024:Ligands; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009429:Netropsin / Q000737:chemistry; D018583:Pliability; D014050:Toluene / Q000737:chemistry; D047391:alpha-Cyclodextrins / Q000737:chemistry*
chemical_list: D001969:Bromobenzenes; D002722:Chlorobenzenes; D004214:Distamycins; D008024:Ligands; D047391:alpha-Cyclodextrins; D014050:Toluene; D009429:Netropsin; C030000:stallimycin; D004247:DNA; C032036:bromobenzene; C031294:chlorobenzene; C032613:alpha-cyclodextrin