基于TEM β-内酰胺酶突变与变构关系分析的抗生素耐药机制

Objective Based on a series of computational bioinformatics and molecular modeling methods, antibiotic resistance mechanism of TEM β-lactamase was explored by studying mutations induced conformational fluctuations of its structure. Methods Firstly, direct coupling analysis was used to predict the direct and indirect coupled residue pairs which determined the conformations of TEM. Then molecular dynamic simulation and conformational frustration estimation were employed to analyze the conformational fluctuations induced by the resistance mutations involved in coupled residue pairs. Finally, druggable biding site identification method, named as Fd-DCA, was adopted to search the TEM surface to find the potential anti-resistance drug design binding sites. Results The strongest couplings were identified to be located within and between the domains of 238-loop and Ω-loop, as well as among the locations of mutant residues of TEM-52, i.e., E104K, G238S and M182T. The molecular conformational change simulation and frustration estimation proved that these couplings played important roles in the formation of the conformations of TEM. A novel druggable allosteric binding site, which was strongly coupled with Ω-loop, was identified eventually. This opened the new way for designing anti-resistance drugs against β-lactamase.