Insights into the structural and functional aspects of rela by molecular modeling and docking calculations.

Abstract

RelA (ppGpp synthetase I) has been reported as an excellent drug target due to its correlation with virulence induction in bacteria. The aim of present investigation is to provide a deeper understanding of the structural and functional aspects of RelA by an in silico-based approach.Molecular models were proposed for the catalytic domain of RelA in two Gram negative bacteria Pseudomonas aeruginosa and Vibrio vulnificus, in former one, RelA contributes to virulence whereas no such data have published in the second case. These models were subjected to docking calculations using ppGpp synthetic analogues.The binding pocket characteristics in RelA are prone to fluctuations due to changes in some crucial interacting residues and this can have a profound influence on the binding interactions with ligands. GRxKH, a cationic motif, was observed to make consistent interactions with inhibitors, hence, suggested to have role in the charge transfer mechanism during signaling cascades.These functional residues/motifs could be key determinants of pharmacological selectivity and specificity in RelA. At the same time, they also demand comprehensive experimental studies like site-directed mutagenesis to demonstrate their involvement in inducing virulence factors.