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ONIOM and FMO‐EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site
Author(s) -
Śliwa Paweł,
Kurczab Rafał,
Bojarski Andrzej J.
Publication year - 2018
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.25617
Subject(s) - oniom , chemistry , allosteric regulation , metabotropic glutamate receptor 1 , stereochemistry , metabotropic glutamate receptor , substituent , ligand (biochemistry) , fragment molecular orbital , molecular orbital , ab initio , computational chemistry , molecule , glutamate receptor , receptor , biochemistry , organic chemistry
The crystal structure of metabotropic glutamate receptor 1 (mGluR1) complexed with 4‐fluoro‐ N ‐(4‐(6‐(isopropylamino)pyrimidin‐4‐yl)thiazol‐2‐yl)‐ N ‐methylbenzamide (FITM, a negative allosteric modulator) and its twelve close structural analogs with a broad spectrum of affinities (2.4 nM < IC 50 > 10 000 nM) were investigated using quantum mechanical methods. The our own N ‐layered integrated molecular orbital and molecular mechanics (ONIOM) was used to optimize the molecular geometries of the receptor with complexed ligands, which were then used to perform the ab initio calculations using the fragment molecular orbitals method with energy decomposition analysis (FMO‐EDA). The results clearly showed that residues Q660 3.28 and/or Y805 6.55 were the anchoring points for all the studied analogs of FITM, while the H‐bond with T815 7.38 determined only the orientation of very active molecules containing an amino substituent in the pyrimidine moiety (e.g., FITM). The orientation of the other parts of ligands resulted from hydrophobic interactions mainly with L757 5.44 , F801 6.51 , or W798 6.48 . The applied ONIOM/FMO–EDA approach facilitated the study of effects related to very small changes in the ligand structure and led to conclusions regarding the significance of individual interactions in the allosteric binding pocket of mGluR1.