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

Jožica Dolenc, Sereina Riniker, Roberto Gaspari, Xavier Daura, Wilfred F. Van Gunsteren

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

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. © 2011 Springer Science+Business Media B.V.
Original languageEnglish
Pages (from-to)709-716
JournalJournal of Computer-Aided Molecular Design
Volume25
DOIs
Publication statusPublished - 1 Aug 2011

Keywords

  • Conformational flexibility
  • DNA-ligand binding
  • Drug design
  • Molecular dynamics
  • α-Cyclodextrin

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