Background: Schizophrenia is a neurodegenerative disorder that occurs worldwide\r\nand can be difficult to diagnose. It is the foremost neurological disorder leading to\r\nsuicide among patients in both developed and underdeveloped countries. D-amino\r\nacid oxidase activator (DAOA), also known as G72, is directly implicated in the\r\nglutamateric hypothesis of schizophrenia. It activates D-amino acid oxidase, which\r\noxidizes D-serine, leading to modulation of the N-methyl-D-aspartate receptor.\r\nMethods: MODELLER (9v10) was utilized to generate three dimensional structures of\r\nthe DAOA candidate gene. The HOPE server was used for mutational analysis. The\r\nMolecular Evolutionary Genetics Analysis (MEGA5) tool was utilized to reconstruct the\r\nevolutionary history of the candidate gene DAOA. AutoDock was used for\r\nprotein-ligand docking and Gramm-X and PatchDock for protein-protein docking.\r\nResults: A suitable template (1ZCA) was selected by employing BLASTp on the basis\r\nof 33% query coverage, 27% identity and E-value 4.9. The Rampage evaluation tool\r\nshowed 91.1% favored region, 4.9% allowed region and 4.1% outlier region in DAOA.\r\nERRAT demonstrated that the predicted model had a 50.909% quality factor.\r\nMutational analysis of DAOA revealed significant effects on hydrogen bonding and\r\ncorrect folding of the DAOA protein, which in turn affect protein conformation.\r\nCiona was inferred as the outgroup. Tetrapods were in their appropriate clusters with\r\nbifurcations. Human amino acid sequences are conserved, with chimpanzee and\r\ngorilla showing more than 80% homology and bootstrap value based on 1000\r\nreplications. Molecular docking analysis was employed to elucidate the binding\r\nmode of the reported ligand complex for DAOA. The docking experiment\r\ndemonstrated that DAOA is involved in major amino acid interactions: the residues\r\nthat interact most strongly with the ligand C28H28N3O5PS2 are polar but uncharged\r\n(Gln36, Asn38, Thr 122) and non-polar hydrophobic (Ile119, Ser171, Ser21, Ala31).\r\nProtein-protein docking simulation demonstrated two ionic bonds and one\r\nhydrogen bond involving DAOA. Lys-7 of the receptor protein interacted with\r\nLys-163 and Asp-2037. Tyr-03 interacted with Arg-286 of the ligand protein and\r\nformed a hydrogen bond.
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