Explicando Ab Initio a Intensidade de Ativação e Antagonismo do Receptor Glutamatérgico GluR2

Abstract

The transmission of nerve impulses occurs through the synapses, involving neurotransmitters and receptors. The ionotropic glutamate receptors GluRs are important ionic channels of the central nervous system, founded in rapid excitation synapses, and related to important cerebral functions like learning and memory. Besides this, GluRs are also associated with important neurological and psychiatric diseases like Alzheimer, Parkinson, epilepsy, cerebral ischemia, amyotrophic lateral sclerosis, and schizophrenia. In this work, we take advantage of the available data in the literature of co-crystallization of the following full agonists glutamate (C5H9NO4) and AMPA (C7H10N2O4), the partial agonist kainate (C10H15NO4) and the antagonist DNQX (C8H2N4O6) with the GluR2 receptor with resolution of 1.9 Å, 1.7 Å, 1.9 Å and 1.8 Å, respectively to study the interaction of these four ligands with GluR2 by means of ab initio computational methods. The absent hydrogens in the GluR2-ligand X-ray diffraction data were inserted through a semi-classical total energy minimization process. Next, the simulations were performed within the scope of the Density Functional Theory (DFT), both in the local density approximation (LDA) as generalized gradient approximation (GGA) for the description of exchange-correlation effects. The use of the molecular fragmentation method with conjugated caps (MFCC) allowed to analyze the interaction between the ligands with each one close and next-closed GluR2 residues. It was also considered the relevance of the screening of the next-closed residues with interact with the ligands, and it was performed an analysis of the interaction energy between the focused residues (close and next-closed) with the atoms of the ligands (results depicted in the BIRD panels), without and with the mediation of water molecules existing in the binding pocket (which allows to determine ab initio the relevance of water in the GluR2-ligands energetic). It was obtained the GluR2-ligand total energy interaction as a function of the distance between the ligand centroid and the residues, which allowed to correlate it to the activation strength and antagonism of the ligands focused. It was demonstrated that it follows the order AMPA > glutamate > kainite > DNQX only when a large enough binding pocket radius is taken into account, explaining the experimental data published on the activation and antagonism of the glutamatergic receptor GluR2 and suggesting the next-closed residues can be important to determine the receptor functioning. For the glutamate, the obtained results point that the most important attractive residues are Arg485, Lys730 (water W39 mediated), Ser654, Leu650 (water W69 mediated), and Lys656 (water W22 mediated); the most important repulsive residues for the glutamate are Glu402 (next-closed water W36 mediated), Glu657 and Asp651 (nex-closed). For AMPA, the most important attractive residues are Arg485, Thr655 (water W134 mediated), Lys730 (water W137 mediated), Lys656 (water W138 mediated), Lys449 and Arg684 (next-closed); the most important repulsive residues for AMPA are Glu402 (water W3 mediated), Asp651 (next-closed, water W96 and W139 mediated), and Glu657 (next-closed, water W140 mediated). For kainate the most important attractive residues are Arg485, Ser654, Thr655 and Arg684 (next-closed); the most important repulsive residues for kainite are Glu402, Glu657 (next-closed, water W78 mediated) and Asp651. For DNQX, the most important attractive residues are Arg485, Glu705 and Tyr450 (water W26 and W137 mediated); the most important repulsive residue for DNQX is Leu498. A pleiade of perspectives related with the obtained results shines, among which one can highlight the possibility to develop glutamatergic agonists and antagonists with specificities related to decrease side effects when used in the treatment of maladies related with the glutamatergic neurotransmission.