title: Exploring the energy landscapes of molecular recognition by a genetic algorithm: analysis of the requirements for robust docking of HIV-1 protease and FKBP-12 complexes.
abstract: Energy landscapes of molecular recognition are explored by performing "semi-rigid" docking of FK-506 and rapamycin with the Fukisawa binding protein (FKBP-12), and flexible docking simulations of the Ro-31-8959 and AG-1284 inhibitors with HIV-1 protease by a genetic algorithm. The requirements of a molecular recognition model to meet thermodynamic and kinetic criteria of ligand-protein docking simultaneously are investigated using a family of simple molecular recognition energy functions. The critical factor that determines the success rate in predicting the structure of ligand-protein complexes is found to be the roughness of the binding energy landscape, in accordance with a minimal frustration principle. The results suggest that further progress in structure prediction of ligand-protein complexes can be achieved by designing molecular recognition energy functions that generate binding landscapes with reduced frustration.
authors.affiliation: Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Verkhivker
authors.forename: P A
authors.initials: PA
authors.lastname: Rejto
authors.forename: D K
authors.initials: DK
authors.lastname: Gehlhaar
authors.forename: S T
authors.initials: ST
authors.lastname: Freer
mesh_terms: D000465:Algorithms; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D006360:Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics; D008957:Models, Genetic; D022021:Tacrolimus Binding Proteins
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D017320:HIV Protease Inhibitors; D006360:Heat-Shock Proteins; D016333:HIV Protease; D022021:Tacrolimus Binding Proteins