title: Direct calculation of the binding free energies of FKBP ligands.
abstract: Direct calculations of the absolute free energies of binding for eight ligands to FKBP protein were performed using the Fujitsu BioServer massively parallel computer. Using the latest version of the general assisted model building with energy refinement (AMBER) force field for ligand model parameters and the Bennett acceptance ratio for computing free-energy differences, we obtained an excellent linear fit between the calculated and experimental binding free energies. The rms error from a linear fit is 0.4 kcal/mol for eight ligand complexes. In comparison with a previous study of the binding energies of these same eight ligand complexes, these results suggest that the use of improved model parameters can lead to more predictive binding estimates, and that these estimates can be obtained with significantly less computer time than previously thought. These findings make such direct methods more attractive for use in rational drug design.
authors.affiliation: Fujitsu Laboratories Ltd., 10-1 Morinosato-Wakamiya, Atsugi 243-0197, Japan. fjtani@labs.fujitsu.com
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujitani
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tanida
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Ito
authors.forename: Guha
authors.initials: G
authors.lastname: Jayachandran
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Snow
authors.forename: Michael R
authors.initials: MR
authors.lastname: Shirts
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorin
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
mesh_terms: D001703:Biophysics / Q000379:methods*; D002627:Chemistry, Physical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D019277:Entropy; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008962:Models, Theoretical; D008968:Molecular Conformation; D011485:Protein Binding; D011487:Protein Conformation; D022021:Tacrolimus Binding Proteins / Q000737:chemistry*; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D008024:Ligands; D022021:Tacrolimus Binding Proteins