Free energy calculations offer insights into the influence of receptor flexibility on ligand–receptor binding affinities
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.
Keywordsα-Cyclodextrin Conformational flexibility Drug design DNA–ligand binding Molecular dynamics
Financial support by the National Centre of Competence in Research (NCCR) in Structural Biology and by grant number 200020-121913 of the Swiss National Science Foundation (SNSF) and by grant number 228076 of the European Research Council (ERC) to W. F. van G., and by grant BIO2007-62954 of the Spanish MEC/FEDER to X. D., and by the Slovenian Research Agency (ARRS), grant number Z1-9576 to J. D., is gratefully acknowledged.
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