title: Entropic and enthalpic contributions to stereospecific ligand binding from enhanced sampling methods.
abstract: The stereoselective binding of R- and S-propranolol to the metabolic enzyme cytochrome P450 2D6 and its mutant F483A was studied using various computational approaches. Previously reported free-energy differences from Hamiltonian replica exchange simulations, combined with thermodynamic integration, are compared to the one-step perturbation approach, combined with local-elevation enhanced sampling, and an excellent agreement between methods was obtained. Further, the free-energy differences are interpreted in terms of enthalpic and entropic contributions where it is shown that exactly compensating contributions obscure a molecular interpretation of differences in the affinity while various reduced terms allow a more detailed analysis, which agree with heuristic observations on the interactions.
authors.affiliation: Department of Material Sciences and Process Engineering, Institute of Molecular Modeling and Simulation at BOKU- University of Natural Resources and Life Sciences , Muthgasse 18, A-1190 Vienna, Austria.
authors.forename: Balder
authors.initials: B
authors.lastname: Lai
authors.forename: Gabor
authors.initials: G
authors.lastname: Nagy
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Garate
authors.forename: Chris
authors.initials: C
authors.lastname: Oostenbrink
mesh_terms: D019943:Amino Acid Substitution; D019295:Computational Biology; D003198:Computer Simulation; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019277:Entropy; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011433:Propranolol / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D008024:Ligands; D050505:Mutant Proteins; D011433:Propranolol; D019389:Cytochrome P-450 CYP2D6