Probing the Structural and Conformational Stability of the Wb-iPGM Enzyme and Role of Mn2+ Ions in Their Catalytic Site

Abstract

Cofactor-independent phosphoglycerate mutase (iPGM) is an indispensable enzyme for most of the nematodes including filarial nematodes. Therefore could be targeted as a vital drug target in Wuchereria bancrofti (Wb) for the treatment of lymphatic filariasis. It catalyzes the inter-conversion between 2-phosphoglycerate and 3-phosphoglycerate in the glycolytic and gluconeogenic pathways. Since, the crystal structure of Wb-iPGM is not available; we have developed the tertiary structure of Wb-iPGM and investigated its structural stability by molecular dynamics simulation (MD) study. Wb-iPGM is linked with cofactors 3-phosphoglycerate (3PGA) and divalent Mn2+ ions. Here, we probe the stability and dynamics of the Wb-iPGM, Wb-iPGM+3PGA, Wb-iPGM+3PGA+Mn2+ and Wb-iPGM+Mn2+ complexes to investigate the role of Mn2+ ions in terms of protein stability and functionality. We investigated Wb-iPGM and their cofactors to get insight into their role in protein. Notably, we provide the first time the molecular organization and the role of cofactors in Wb-iPGM proteins using MD and free energy landscape. Interestingly, we had observed domain motions between α and β domains of Wb-iPGM when they were in bound and free form with 3PGA molecules using DynDom. Domain motion study revealed opening and partial closing mechanisms of these domains in the presence and absence of Mn2+ ions in Wb-iPGM and 3PGA complexes. This study provides insight into the molecular mechanisms of Mn2+ for the secondary structure establishment and their significant role in the catalytic site.