Journal
STRUCTURE
Volume 15, Issue 10, Pages 1203-1214Publisher
CELL PRESS
DOI: 10.1016/j.str.2007.07.015
Keywords
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Funding
- NCI NIH HHS [CA 93577, R01 CA093577-05, R01 CA093577] Funding Source: Medline
- NIGMS NIH HHS [R01 GM062342-08, R01 GM062342, GM 62342] Funding Source: Medline
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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. Theapo 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 S1 S2 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 S1 S2 in open conformations. Free energy landscapes were also computed for the glutamate-bound T686A and T686S S1 S2 mutants, and the results elaborate on findings from experimental functional studies.
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