title: Fast, metadynamics-based method for prediction of the stereochemistry-dependent relative free energies of ligand-receptor interactions.
abstract: The computational approach applicable for the molecular dynamics (MD)-based techniques is proposed to predict the ligand-protein binding affinities dependent on the ligand stereochemistry. All possible stereoconfigurations are expressed in terms of one set of force-field parameters [stereoconfiguration-independent potential (SIP)], which allows for calculating all relative free energies by only single simulation. SIP can be used for studying diverse, stereoconfiguration-dependent phenomena by means of various computational techniques of enhanced sampling. The method has been successfully tested on the β2-adrenergic receptor (β2-AR) binding the four fenoterol stereoisomers by both metadynamics simulations and replica-exchange MD. Both the methods gave very similar results, fully confirming the presence of stereoselective effects in the fenoterol-β2-AR interactions. However, the metadynamics-based approach offered much better efficiency of sampling which allows for significant reduction of the unphysical region in SIP.
authors.affiliation: Department of Chemistry, Faculty of Pharmacy, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, W. Chodzki Street, 4a, 20-093, Lublin, Poland.
authors.forename: Anita
authors.initials: A
authors.lastname: Plazinska
authors.forename: Wojciech
authors.initials: W
authors.lastname: Plazinski
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D005280:Fenoterol / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D005280:Fenoterol
keywords: affinity constant; chiral ligands; ligand; molecular dynamics; protein binding; replica-exchange molecular dynamics