A study on structural perturbations in MTHFR Ala222 Val mutant by bioinformatics and systems biology approach

Abstract

Methylenetetrahydrofolatereductase MTHFR protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate the active form of folic acid essential for several molecular functions Experimental studies have shown that the C677T mutation does not affect the kinetic properties of MTHFR but inactivates the protein by increasing Flavin Adenine Dinucleotide FAD loss A systematic Meta analysis to explore the association of MTHFR C677T mutation with Ischemic stroke Down syndrome Neural tube defects Meta-analysis results revealed that subjects with C677T mutation of MTHFR have 30 per cent higher risk developing Ischemic stroke when compared to controls there was a 17 per cent higher risk of giving birth to off springs with Down Syndrome and 41 per cent higher risk of giving birth to off springs with NTD compared to controls The lack of crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation computational modeling provides a suitable alternative The 3D structure of human MTHFR protein was obtained through homology modeling Subsequently the modeled structure was docked with FAD using Glide which revealed a very good binding affinity authenticated by a Glide XP score of 10 point 3983 kcal mol 1 The MTHFR was mutated by changing Alanine 222 to Valine The wild type MTHFR FAD complex and the Ala222Val mutant MTHFR FAD complex were subjected to molecular dynamics simulation over 50 ns period The average difference in backbone root mean square deviation RMSD between wild and mutant variant was found to be 11 Å The FAD binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility Multilayer Perceptron to Classify Wild-Type and Mutant MTHFR by taking RMSDs of C Backbone Side Chain and Ligand RMSDs through 50 ns MD Simulation was found to show overall accuracy of 96point 4 per cent newline