In Silico Structural Modeling of Wildtype and Mutant PRODH Proteins Involved in Psychiatric Disorder.
Abstract Proline dehydrogenase is an important mitochondrial enzyme that is encoded by the PRODH gene. Biologically, a mutation in this gene affects the activity of proline dehydrogenase enzyme that is normally involved in conversion of proline to glutamate. However, its reduced or null activity leads to excess quantity of proline in the body, which results in different psychiatric phenotypes along with intellectual disability. In the present study, we performed in silico analysis on all reported mutations of PRODH. The 3D models of normal and mutant PRODH were predicted using I-TASSER. The predicted structures were visualized and superimposed using chimera 1.13.1. The CASTp was used to identify active sites in modelled proteins. Protein-protein docking was done with Cluspro, while protein-substrate docking was done with Auto Dock 1.5.6 and-MGL tools and the results were visualized using LigPlus+ v.2.2 and Discovery studio 2020 respectively. Alignment of 3D models (mutant with wildtype) revealed that Arg185Gln (73.83 % ) and Gln19Ter (6.25% ) had the highest and lowest similarity indices, respectively. Enzyme pocket prediction identified three largest sites, with the second largest active site pocket containing substrate proline binding residues Leu527, Tyr548, and Arg563. Moreover, docking of mutant and wildtype PRODH with its close interactor “ALDH4A1” showed differences with respect to number, position, and nature of interacting amino acids residues. We observed that the nature of amino acid substitution and the number of bonds affect the binding of proline molecule with proline dehydrogenase enzyme, and therefore, affect its biological activity.