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Interplay between structural rigidity and electrostatic interactions in the ligand binding domain of GluR2
Author(s) -
Mamonova Tatyana,
Speranskiy Kirill,
Kurnikova Maria
Publication year - 2008
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22090
Subject(s) - molecular dynamics , chemistry , structural rigidity , hydrogen bond , crystallography , salt bridge , rigidity (electromagnetism) , hinge , ligand (biochemistry) , transition state , protein structure , intramolecular force , biophysics , stereochemistry , chemical physics , receptor , molecule , computational chemistry , materials science , mechanical engineering , biochemistry , geometry , mathematics , organic chemistry , biology , mutant , engineering , composite material , gene , catalysis
Using molecular dynamics (MD) simulations, computational protein modifications, and a novel theoretical methodology that determines structural rigidity/flexibility (the FIRST algorithm), we investigate how molecular structure and dynamics of the glutamate receptor ligand binding domain (GluR2 S1S2) facilitate its conformational transition. S1S2 is a two‐lobe protein, which undergoes a cleft closure conformational transition upon binding an agonist in the cleft between the two lobes; hence it is expected that the mechanism of this conformational transition can be characterized as a hinge‐type. However, in the rigidity analysis one lobe of the protein is identified as a single rigid cluster while the other one is structurally flexible, inconsistent with a presumed mechanical hinge mechanism. Instead, we characterize the cleft‐closing transition as a load and lock mechanism. We find that when two cross‐cleft hydrogen bonds are disrupted the protein undergoes a rapid cleft opening transition. At the same time, the dynamical behavior of the cleft in the presence of the glutamate ligand is only weakly affected by the S652 peptide bond in its flipped conformation observed in the crystal structure. The residue E705 plays significant role in stabilization of the closed conformation via electrostatic interactions. The presence of the E705‐K730 salt bridge seems to correlate strongly withthe cleft opening transition in the MD simulations. Proteins 2008. © 2008 Wiley‐Liss, Inc.