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Homology modeling and molecular dynamics simulations of the glycine receptor ligand binding domain
Author(s) -
Speranskiy Kirill,
Cascio Michael,
Kurnikova Maria
Publication year - 2007
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.21251
Subject(s) - homology modeling , glycine receptor , docking (animal) , chemistry , molecular dynamics , biophysics , protein structure , protein superfamily , binding site , protein subunit , stereochemistry , biochemistry , biology , glycine , amino acid , computational chemistry , nursing , medicine , gene , enzyme
We present a homology based model of the ligand binding domain (LBD) of the homopentameric alpha1 glycine receptor (GlyR). The model is based on multiple sequence alignment with other members of the nicotinicoid ligand gated ion channel superfamily and two homologous acetylcholine binding proteins (AChBP) from the freshwater (Lymnaea stagnalis) and saltwater (Aplysia californica) snails with known high resolution structure. Using two template proteins with known structure to model three dimensional structure of a target protein is especially advantageous for sequences with low homology as in the case presented in this paper. The final model was cross‐validated by critical evaluation of experimental and published mutagenesis, functional and other biochemical studies. In addition, a complex structure with strychnine antagonist in the putative binding site is proposed based on docking simulation using Autodock program. Molecular dynamics (MD) simulations with simulated annealing protocol are reported on the proposed LBD of GlyR, which is stable in 5 ns simulation in water, as well as for a deformed LBD structure modeled on the corresponding domain determined in low‐resolution cryomicroscopy structure of the alpha subunit of the full‐length acetylcholine receptor (AChR). Our simulations demonstrate that the beta‐sandwich central core of the protein monomer is fairly rigid in the simulations and resistant to deformations in water. Proteins 2007. © 2007 Wiley‐Liss, Inc.