Computational prediction of the pathogenic variants of arachidonate 5-lipoxygenase activating protein using Molecular Dynamics simulation

Abstract

The arachidonate 5-lipoxygenase activating protein (ALOX5AP) regulates leukotrienes (LTs) synthesis. LTs are involved in inflammation which is implicated in cardiovascular diseases (CVDs) and stroke. Variations in ALOX5AP gene are associated with CVDs, stroke and others because of their possible effects on ALOX5AP stability and function. In this study we investigated with molecular dynamics (MD) simulation the structural impacts of L12F, A56V, G75R, and G87R variants on ALOX5AP. We employed an array of bioinformatics techniques, including SIFT, PolyPhen-2, PANTHER, SNPs&GO, PhD-SNP, i-Mutant, MuPro, MutPred, ConSurf, and GROMACS. Results showed that the L12F variant increased structural compactness, as indicated by diminished solvent accessibility, a reduced radius of gyration, and a decrease in hydrogen bonding capacity. The A56V variant destabilized the ALOX5AP, demonstrating elevated root mean square deviation (RMSD), augmented solvent-accessible surface area, and diminished ALOX5AP compactness. The G75R and G87R variants exhibited mild effects on ALOX5AP wildtype. However, simulation trajectory snapshots results indicated G75R and G87R variants induce instability leading to structural perturbations of ALOX5AP probably due to the charge of arginine introduced by the G75R and G87R mutation. The G75R and G87R variants potentially influence ALOX5AP dynamics, stability, and function. These results require further verification in future case-control and protein functional studies.