title: Reduced curvature of ligand-binding domain free-energy surface underlies partial agonism at NMDA receptors.
abstract: NMDA receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the central nervous system. Partial agonists elicit submaximal channel activation, but crystal structures of the ligand-binding domains (LBDs) bound with partial and full agonists show little difference. To uncover the molecular mechanism for partial agonism, here we computed the free-energy surfaces of the GluN1 (an obligatory subunit of NMDA receptors) LBD bound with a variety of ligands. The free-energy minima are similarly positioned for full and partial agonists, but the curvatures are significantly reduced in the latter case, indicating higher probabilities for sampling conformations with a not fully closed domain cleft. The free-energy surfaces for antagonists have both shifted minima and further reduced curvatures. Reduced curvature of free-energy surface appears to explain well the partial agonism at NMDA receptors and may present a unique paradigm in producing graded responses for receptors in general.
authors.affiliation: Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA. Electronic address: hzhou4@fsu.edu.
authors.forename: Huan-Xiang
authors.initials: HX
authors.lastname: Zhou
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D054333:Drug Partial Agonism; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate