Dynamical Behavior of β-Lactamases and Penicillin- Binding Proteins in Different Functional States and Its Potential Role in Evolution

β-Lactamases are enzymes produced by bacteria to hydrolyze β-lactam-based antibiotics, and pose serious threat to public health through related antibiotic resistance. Class A β-lactamases are structurally and functionally related to penicillin-binding proteins (PBPs). Despite the extensive studies of the structures, catalytic mechanisms and dynamics of both β-lactamases and PBPs, the potentially different dynamical behaviors of these proteins in different functional states still remain elusive in general. In this study, four evolutionarily related proteins, including TEM-1 and TOHO-1 as class A β-lactamases, PBP-A and DD-transpeptidase as two PBPs, are subjected to molecular dynamics simulations and various analyses to characterize their dynamical behaviors in different functional states. Penicillin G and its ring opening product serve as common ligands for these four proteins of interest. The dynamic analyses of overall structures, the active sites with penicillin G, and three catalytically important residues commonly shared by all four proteins reveal unexpected cross similarities between Class A β-lactamases and PBPs. These findings shed light on both the hidden relations among dynamical behaviors of these proteins and the functional and evolutionary relations among class A β-lactamases and PBPs.

Abstract licence: CC BY

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