title: Free energies of binding of R- and S-propranolol to wild-type and F483A mutant cytochrome P450 2D6 from molecular dynamics simulations.
abstract: Detailed molecular dynamics (MD) simulations have been performed to reproduce and rationalize the experimental finding that the F483A mutant of CYP2D6 has lower affinity for R-propranolol than for S-propranolol. Wild-type (WT) CYP2D6 does not show this stereospecificity. Four different approaches to calculate the free energy differences have been investigated and were compared to the experimental binding data. From the differences between calculations based on forward and backward processes and the closure of thermodynamic cycles, it was clear that not all simulations converged sufficiently. The approach that calculates the free energies of exchanging R-propranolol with S-propranolol in the F483A mutant relative to the exchange free energy in WT CYP2D6 accurately reproduced the experimental binding data. Careful inspection of the end-points of the MD simulations involved in this approach, allowed for a molecular interpretation of the observed differences.
authors.affiliation: Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Leiden Amsterdam Center for Drug Research (LACDR), Vrije Universiteit, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Chris
authors.initials: C
authors.lastname: Oostenbrink
authors.forename: Peter H J
authors.initials: PH
authors.lastname: Keizers
authors.forename: Barbara M A
authors.initials: BM
authors.lastname: van Vugt-Lussenburg
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Commandeur
authors.forename: Nico P E
authors.initials: NP
authors.lastname: Vermeulen
mesh_terms: D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008968:Molecular Conformation; D009154:Mutation; D011433:Propranolol / Q000737:chemistry*; D011485:Protein Binding; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D011433:Propranolol; D019389:Cytochrome P-450 CYP2D6