title: Towards understanding the mechanisms of molecular recognition by computer simulations of ligand-protein interactions.
abstract: The thermodynamic and kinetic aspects of molecular recognition for the methotrexate (MTX)-dihydrofolate reductase (DHFR) ligand-protein system are investigated by the binding energy landscape approach. The impact of 'hot' and 'cold' errors in ligand mutations on the thermodynamic stability of the native MTX-DHFR complex is analyzed, and relationships between the molecular recognition mechanism and the degree of ligand optimization are discussed. The nature and relative stability of intermediates and thermodynamic phases on the ligand-protein association pathway are studied, providing new insights into connections between protein folding and molecular recognition mechanisms, and cooperativity of ligand-protein binding. The results of kinetic docking simulations are rationalized based on the thermodynamic properties determined from equilibrium simulations and the shape of the underlying binding energy landscape. We show how evolutionary ligand selection for a receptor active site can produce well-optimized ligand-protein systems such as MTX-DHFR complex with the thermodynamically stable native structure and a direct transition mechanism of binding from unbound conformations to the unique native structure.
authors.affiliation: Agouron Pharmaceuticals Inc., 3301 North Torrey Pines Court, La Jolla, CA 92037-1022, USA. verk@agouron.com
authors.forename: G M
authors.initials: GM
authors.lastname: Verkhivker
authors.forename: P A
authors.initials: PA
authors.lastname: Rejto
authors.forename: D
authors.initials: D
authors.lastname: Bouzida
authors.forename: S
authors.initials: S
authors.lastname: Arthurs
authors.forename: A B
authors.initials: AB
authors.lastname: Colson
authors.forename: S T
authors.initials: ST
authors.lastname: Freer
authors.forename: D K
authors.initials: DK
authors.lastname: Gehlhaar
authors.forename: V
authors.initials: V
authors.lastname: Larson
authors.forename: B A
authors.initials: BA
authors.lastname: Luty
authors.forename: T
authors.initials: T
authors.lastname: Marrone
authors.forename: P W
authors.initials: PW
authors.lastname: Rose
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D019143:Evolution, Molecular; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D046911:Macromolecular Substances; D008727:Methotrexate / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D009010:Monte Carlo Method; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D012641:Selection, Genetic; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D005493:Folic Acid Antagonists; D008024:Ligands; D046911:Macromolecular Substances; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate