title: Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor.
abstract: Elucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein-ligand binding, especially the drug recognition of GPCRs.
authors.affiliation: Department of Chemistry and Biochemistry,University of California at San Diego,La Jolla,CA 92093,USA.
authors.forename: Kalli
authors.initials: K
authors.lastname: Kappel
authors.affiliation: Howard Hughes Medical Institute,University of California at San Diego,La Jolla,CA 92093,USA.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Miao
authors.affiliation: Department of Chemistry and Biochemistry,University of California at San Diego,La Jolla,CA 92093,USA.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000109:Acetylcholine / Q000737:chemistry; D000495:Allosteric Site; D001115:Arecoline / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D043585:Receptor, Muscarinic M2 / Q000737:chemistry; D043587:Receptor, Muscarinic M3 / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D000069447:Tiotropium Bromide / Q000737:chemistry
chemical_list: D008024:Ligands; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043562:Receptors, G-Protein-Coupled; D001115:Arecoline; D000109:Acetylcholine; D000069447:Tiotropium Bromide
keywords: G-protein coupled receptor; Ligand binding; M3 muscarinic receptor; accelerated molecular dynamics; enhanced sampling