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.
Original language | English (US) |
---|---|
Pages (from-to) | 1203-1214 |
Number of pages | 12 |
Journal | Structure |
Volume | 15 |
Issue number | 10 |
DOIs | |
State | Published - Oct 16 2007 |
Externally published | Yes |
Keywords
- PROTEINS
- SIGNALING
ASJC Scopus subject areas
- Structural Biology
- Molecular Biology