Mechanism of pH-induced conformational changes in MurE ligase obtained from Salmonella enterica serovar Typhi

AUTHORS

Khan FI, Hassan F, Ali H, Lai D

ABSTRACT

MurE ligase is a vital enzyme in the peptidoglycan pathway. During biosynthesis of the peptidoglycan precursor, the MurE ligase adds meso-diaminpimelate to peptidoglycans. This enzyme is crucial for the viability of bacterial cells and their absence in higher eukaryotes make them a striking target for development of antimicrobials drugs. Previous experimental studies on MurE ligase of Salmonella enterica serovar Typhi suggested conformational variations linked with increasing concentration of GdmCl and urea. In the present study, the three-dimensional structure of MurE ligase of S. enterica serovar Typhi was predicted and several pH based 100 ns molecular dynamics (MD) simulations were performed to better understand its conformational profile at molecular level. The results suggested a robust conformational pH dependence of MurE ligase. The average number of hydrogen bonds and amino acid residues involved in structure formation were found to be more at higher pH. Further, the Gibbs free energy values of MurE ligase at different pH conditions suggested that the MurE ligase exhibited a more rugged or uneven free energy surface at lower pH. The overall results suggested that MurE ligase shows higher structure deviations at lower pH, and maintained its bio-active structural conformation at higher pH during 100 ns MD simulations. This study provides a significant understanding of conformational changes in MurE ligase that can be used in the development of antibacterial drugs.

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