Deciphering the role of sulfonamides and molecular basis of thioredoxin domain dynamics through comparative simulations

Abstract

DsbA, a thioredoxin periplasmic protein was prioritized based on subtractive proteomics and immunoinformatics in-depth investigation of Providencia rettgeri proteome. It is an important member of the protein family thioredoxins that catalyzes disulfide bond formation and acts as a folding catalyst for multiple categories of virulence factors. Herein, we performed the molecular dynamics (MD) simulation analysis of synthetic analogues of ubiquinone (dimedone derivatives) that inhibit disulfide bond formation (IC50 ~ 1 μM) catalyzed by E. coli DsbA: DsbB and in comparison propose a sulfonamide comprising compound from the Chembridge library. Both the structures were confined to crystal water molecules and placed in a 5-Å shell of water. The enzyme in solution underwent ligand-induced conformational changes, which appeared to correspond to position shifts in the equilibrium in the crystallographically defined thioredoxin domains. Dimedone derivative eventually drifted away from the thioredoxin domain and shifted to the conserved hydrophobic patch exposing itself to interact preferably with the solvent or the membrane protein DsbB. Comparatively, a Chembridge compound 10,005,560 exhibited strong hydrogen bonding and π- π stacking with the residues ASN155 and PHE56 while moving towards the thioredoxin domain and revealing stability till 250 ns. This positional shift relative to the thioredoxin domain was further analyzed through advanced Radial distribution function (RDF) and Axial frequency distribution (AFD) analyses to confirm the substantial collaboration of sulfonamide core like structures, which could be a starting point into the development of potential DsbA: DsbB inhibitors.