Event Title
Computational Modeling of Pro227Ser Mutant of OXA-24 Beta-Lactamase: Enzyme Dynamics Contributes to Ligand Selectivity Switch
Location
Hager-Lubbers Exhibition Hall
Description
Beta-lactamases are bacterial enzymes that mediate one of major antibiotic resistance mechanisms. Class D (OXA) beta-lactamases have been evolving rapidly over the last decade and are characterized by a remarkable diversity of sequence and antibiotic profiles. OXA-24 is of particular importance among class D enzymes as it is able to hydrolyze carbapenems, the newest and most important family of beta-lactam antibiotics that are used to treat complicated infections caused by resistant strains. One of the OXA-24 variants, a single amino-acid ProSer mutant, is also able to hydrolyze third generation cephalosporins - in addition to carbapanems. In this study we employed Molecular Dynamics simulations of OXA-24 wild type and P227S mutant to elucidate the mechanism of this remarkable expansion of catalytic profile observed in the mutant. Our data show that the mutation affects significantly the enzyme’s both local and global dynamics. The overall flexibility of the loop harboring the mutation is reduced and the new hydrogen bond center impacts the entire hydrogen bond network in this. We also show a change in the loop conformational ensemble: although the flexibility of the loop is reduced, the new conformational states of the affected loop facilitate cephalosporin binding. These results allow us to better understand the dynamics-based mechanisms of evolution of function in class D beta-lactamases.
Computational Modeling of Pro227Ser Mutant of OXA-24 Beta-Lactamase: Enzyme Dynamics Contributes to Ligand Selectivity Switch
Hager-Lubbers Exhibition Hall
Beta-lactamases are bacterial enzymes that mediate one of major antibiotic resistance mechanisms. Class D (OXA) beta-lactamases have been evolving rapidly over the last decade and are characterized by a remarkable diversity of sequence and antibiotic profiles. OXA-24 is of particular importance among class D enzymes as it is able to hydrolyze carbapenems, the newest and most important family of beta-lactam antibiotics that are used to treat complicated infections caused by resistant strains. One of the OXA-24 variants, a single amino-acid ProSer mutant, is also able to hydrolyze third generation cephalosporins - in addition to carbapanems. In this study we employed Molecular Dynamics simulations of OXA-24 wild type and P227S mutant to elucidate the mechanism of this remarkable expansion of catalytic profile observed in the mutant. Our data show that the mutation affects significantly the enzyme’s both local and global dynamics. The overall flexibility of the loop harboring the mutation is reduced and the new hydrogen bond center impacts the entire hydrogen bond network in this. We also show a change in the loop conformational ensemble: although the flexibility of the loop is reduced, the new conformational states of the affected loop facilitate cephalosporin binding. These results allow us to better understand the dynamics-based mechanisms of evolution of function in class D beta-lactamases.