Stacking interaction and its role in kynurenic acid binding to glutamate ionotropic receptors

Abstract

Stacking interaction is known to play an important role in protein folding, enzyme-substrate and ligand-receptor complex formation. It has been shown to make a contribution into the aromatic antagonists binding with glutamate ionotropic receptors (iGluRs), in particular, the complex of NMDA receptor NR1 subunit with the kynurenic acid (KYNA) derivatives. The specificity of KYNA binding to the glutamate receptors subtypes might partially result from the differences in stacking interaction. We have calculated the optimal geometry and binding energy of KYNA dimers with the four types of aromatic amino acid residues in Rattus and Drosophila ionotropic iGluR subunits. All ab initio quantum chemical calculations were performed taking into account electron correlations at MP2 and MP4 perturbation theory levels. We have also investigated the potential energy surfaces (PES) of stacking and hydrogen bonds (HBs) within the receptor binding site and calculated the free energy of the ligand-receptor complex formation. The energy of stacking interaction depends both on the size of aromatic moieties and the electrostatic effects. The distribution of charges was shown to determine the geometry of polar aromatic ring dimers. Presumably, stacking interaction is important at the first stage of ligand binding when HBs are weak. The freedom of ligand movements and rotation within receptor site provides the precise tuning of the HBs pattern, while the incorrect stacking binding prohibits the ligand-receptor complex formation.

Combination of Hypomorphic Mutations of the Drosophila Homologues of Aryl Hydrocarbon Receptor and Nucleosome Assembly Protein Family Genes Disrupts Morphogenesis, Memory and Detoxification

“…Such interactions may have developed during the evolution of multi-cellular organisms in order to avoid toxicity in the environment and became employed by cells and organisms at various stages of development and vital activity. AHR-mediated response to potentially toxic components of environment may have facilitated both adaption to a new ecological niche and developing aversion to dangerous food ingredients at different steps of evolution [32], [33].…”

3-Hydroxykynurenine in Regulation of Drosophila Behavior: The Novel Mechanisms for Cardinal Phenotype Manifestations

“…Kynurenic acid (KYNA) is a non-specific iGluR (Kessler et al, 1989) and α7 nicotinic acetylcholine receptor (Hilmas et al, 2001) antagonist. It can interact with both mammalian and Drosophila iGluR receptors (Zhuravlev et al, 2012), ameliorating excitotoxicity. 3-hydroxykynurenine (3-НОК) and 3-hydroxyanthranilic acid (3-HAA) inhibit lipid peroxidation (Christen et al, 1990;Zhuravlev et al, 2016).…”

Role of kynurenines in regulation of behavior and memory processes in Drosophila

“…При этом у сn в обоих случаях наблюдается стабильное снижение двигательной активности, вероятно, вследствие накопления ингибитора ЦНС KYNA. С помощью методов компьютерного моделирования было показано, что KYNA способна связываться с NR1 NMDAR дрозофилы с константой связи, близкой к таковой у млекопитающих (Zhuravlev et al 2012).…”