Alterations in conformational topology and interaction dynamics caused by L418A mutation leads to activity loss of Mycobacterium tuberculosis isocitrate lyase.

Mycobacterium tuberculosis isocitrate lyase (MtbICL) is a key enzyme of the glyoxylate cycle that catalyzes the cleavage of isocitrate to succinate and glyoxylate and is a potential antituberculosis drug target. The aim of this research was to explore the structural alterations induced by L418A point mutation that caused the loss of enzyme activity. In-depth structural analyses were carried out for understanding the influence of L418A mutation using techniques, viz. molecular dynamics, principal component analysis, time-dependent secondary structure, residue interaction network and molecular docking. Since L418A mutation site is structurally far from the active site, it cannot influence the binding of the substrate directly. Our results showed that collective motions, residual mobility, and flexibility of the enzyme increased upon mutation. The mutated residue changed the global conformational dynamics of the system along with the residue-residue interaction network, leading to a loss of the enzyme activity. The docking results suggest that L418A mutation influenced the binding interactions of the substrate with several residues in the active site of MtbICL. This study provides information on the structural dynamics of MtbICL and highlights the importance of residue level interactions in the protein. Thus, our results may provide significant guidance to the scientific community engaged in designing potent inhibitors targeting MtbICL.