Exploring the conformational changes of the ATP binding site of gyrase B from Escherichia coli complexed with different established inhibitors by using molecular dynamics simulation: Protein–ligand interactions in the light of the alanine scanning and fre

Currently, bacterial diseases cause a death toll around 2 million people a year encouraging the search for new antimicrobial agents. DNA gyrase is a well-established antibacterial target consisting of two subunits, GyrA and GyrB, in a heterodimer A2B2. GyrA is involved in DNA breakage and reunion and GyrB catalyzes the hydrolysis of ATP. The GyrB subunit from Escherichia coli has been investigated, namely the ATP binding pocket both considering the protein without ligands and bound with the inhibitors clorobiocin, novobiocin and 5′-adenylyl-β-γ-imidodiphosphate. The stability of the systems was studied by molecular dynamics simulation with the further analysis of the time dependent root-mean-square coordinate deviation (RMSD) from the initial structure, and temperature factors. Moreover, exploration of the conformational space of the systems during the MD simulation was carried out by a clustering data mining technique using the average-linkage algorithm. Recognizing the key residues in the binding site of the enzyme that are involved in the binding mode with the aforementioned inhibitors was investigated by using two techniques: free energy decomposition and computational alanine scanning.The results from these simulations highlight the important residues in the ATP binding site and can be useful in the design process of potential new inhibitors.

Figure optionsDownload high-quality image (228 K)Download as PowerPoint slideResearch highlights▶ From the molecular dynamics simulations the flexible and rigid parts are identified in the gyrase B. ▶ The performed free energy and ala scanning calculations highlight the important residues in the ATP binding pocket. ▶ The results described in this article are very useful in the design process of new inhibitors acting on gyrase B.