title: The free energy landscapes governing conformational changes in a glutamate receptor ligand-binding domain.
abstract: Ionotropic glutamate receptors are ligand-gated transmembrane ion channels activated by the binding of glutamate. The free energy landscapes governing the opening/closing of the GluR2 S1S2 ligand-binding domain in the apo, DNQX-, and glutamate-bound forms are computed by using all-atom molecular dynamics simulations with explicit solvent, in conjunction with an umbrella sampling strategy. The apo S1S2 easily accesses low-energy conformations that are more open than observed in X-ray crystal structures. A free energy of 9-12 kcal/mol becomes available upon glutamate binding for driving conformational changes in S1S2 associated with receptor activation. Small-angle X-ray scattering profiles calculated from computed ensemble averages agree better with experimental results than profiles calculated from static X-ray crystal structures. Water molecules in the cleft may contribute to stabilizing the apo S1S2 in open conformations. Free energy landscapes were also computed for the glutamate-bound T686A and T686S S1S2 mutants, and the results elaborate on findings from experimental functional studies.
authors.affiliation: Institute for Molecular Pediatric Sciences, Department of Biochemistry and Molecular Biology, Ellen and Melvin Gordon Center for Integrative Science, The University of Chicago, 929 East 57(th) Street, Chicago, IL 60637, USA.
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Lau
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
mesh_terms: D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011810:Quinoxalines / Q000737:chemistry / Q000378:metabolism; D018091:Receptors, AMPA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D053838:Scattering, Small Angle; D013816:Thermodynamics; D014961:X-Ray Diffraction
chemical_list: D001059:Apoproteins; D008024:Ligands; D011810:Quinoxalines; D018091:Receptors, AMPA; D018698:Glutamic Acid; C056723:FG 9041; C104722:glutamate receptor ionotropic, AMPA 2