title: Binding free energy prediction in strongly hydrophobic biomolecular systems.
abstract: We present a comparison of various computational approaches aiming at predicting the binding free energy in ligand-protein systems where the ligand is located within a highly hydrophobic cavity. The relative binding free energy between similar ligands is obtained by means of the thermodynamic integration (TI) method and compared to experimental data obtained through isothermal titration calorimetry measurements. The absolute free energy of binding prediction was obtained on a similar system (a pyrazine derivative bound to a lipocalin) by TI, potential of mean force (PMF) and also by means of the MMPBSA protocols. Although the TI protocol performs poorly either with an explicit or an implicit solvation scheme, the PMF calculation using an implicit solvation scheme leads to encouraging results, with a prediction of the binding affinity being 2 kcal mol(-1) lower than the experimental value. The use of an implicit solvation scheme appears to be well suited for the study of such hydrophobic systems, due to the lack of water molecules within the binding site.
authors.affiliation: LCMBA, Faculté des sciences de Nice-Sophia Antipolis, Centre National de la Recherche Scientifique, UMR 6001, Universitè de Nice-Sophia-Antipolis, UFR Sciences, Parc Valrose, 28, avenue Valrose, 06108 Nice Cedex 2, France.
authors.forename: Landry
authors.initials: L
authors.lastname: Charlier
authors.forename: Claude
authors.initials: C
authors.lastname: Nespoulous
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Serge
authors.initials: S
authors.lastname: Antonczak
authors.forename: Jérome
authors.initials: J
authors.lastname: Golebiowski
mesh_terms: D001665:Binding Sites; D002151:Calorimetry; D054834:Lipocalins / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011719:Pyrazines / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D054834:Lipocalins; D011719:Pyrazines