The Free Energy Landscapes Governing Conformational Changes in a Glutamate Receptor Ligand-Binding Domain

Albert Y. Lau, Benoît Roux

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)1203-1214
Number of pages12
JournalStructure
Volume15
Issue number10
DOIs
StatePublished - Oct 16 2007
Externally publishedYes

Keywords

  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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