Conformational transition of Acinetobacter baumannii KdsC enzyme and the role of magnesium in binding: An insight from comparative molecular dynamics simulation and its implications in novel antibiotics design

Abstract

The 3-deoxy-d-manno-octulosonate 8-phosphate phosphatase (KdsC) catalyzes the hydrolysis of 3-deoxy-d-manno-octulosonate 8-phosphate (KDO 8-P) to 3-deoxy-d-manno-octulosonate (KDO) and inorganic phosphate in KDO biosynthesis pathway of Gram-negative bacteria lipopolysaccharide (LPS) hydrophobic lipid-A core. The essentiality of KDO for bacterial cell viability presents the possibility of its targeting to develop broad-spectrum antibacterial agents. In this study, a receptor based virtually screening method was put forward to identify novel lead inhibitory molecules for KdsC enzyme. Dynamics evaluation in solution revealed three complexes: Asinex-1197, Asinex-1705, and Asinex-1710 from Asinex antibacterial library as highly stable, involving conformational transition from open to close upon lead molecules binding and eloquent role of active pocket magnesium towards inhibitors binding and movements. Interconversion of local secondary structure elements in sequence region of Asp192-Asp208 covering motif β-turn, β-hairpin, and β-sheets is seen recurrently that could be in all likelihood of the pressure excreted on this region during closing conformation event or magnesium driven inhibitor adjustments. The binding free energy estimation predicted gas phase energy for all the three complexes dominating with major contribution from van der Waals energy (in case of Asinex-1705 and Asinex-1710) and balanced contributions of both electrostatic and van der Waals (in case of Asinex-1197). Key residues-scanning shortlisted Leu45, Asp185, Gy188, Arg231, and Lys255 as vital in the interaction network of magnesium and inhibitors at the binding site. Their crucial roles in net binding energy were reaffirmed via in silico site directed alanine scanning method. The filtered hits might be useful to further scaffolds addition and structural optimization to yield high affinity binders of KdsC enzyme, whose inhibition, in turn, will disrupt the outer membrane synthesis.