Molecular dynamics analysis of the effects of GTP, GDP, and benzimidazole derivative on structural dynamics of a cell division protein FtsZ from Mycobacterium tuberculosis.

The prevailing multi-drug resistance in Mycobacterium tuberculosis continues to remain one of the main challenges to combat tuberculosis. Hence, it becomes imperative to focus on novel drug targets. Filamenting temperature-sensitive mutant Z (FtsZ) is an essential cell division protein, a eukaryotic tubulin homologue and a promising drug target. During cytokinesis, FtsZ polymerises in the presence of GTP to form Z-ring and recruits other proteins at this site that eventually lead to the formation of daughter cells. Benzimidazoles were experimentally shown to inhibit Mtb-FtsZ, with one of the benzimidazole derivatives, M1, being reported to have the minimum inhibitory concentration (MIC) value of 3.13µg/ml. In the present study, mechanism of destabilization of FtsZ in the presence of M1 was computationally investigated in the presence of its substrate GTP/GDP employing Molecular dynamics (MD) simulation analysis, principal component analysis (PCA), molecular mechanics combined with the generalized Born and surface area continuum salvation (MM-GBSA), and density functional theory (DFT). From the analyses it is proposed that binding of M1 in the inter-domain cleft induces structural changes in the GTP binding region that affect GTP binding, thus switching the preference of this protein towards depolymerised state and eventually inhibiting the cell division. Hence, this study provides mechanistic insights into the design of novel benzimidazole inhibitors against Mtb-FtsZ.