Molecular Dynamics Simulations of Antibiotic Ceftaroline at the Allosteric Site of Penicillin-Binding Protein 2a (PBP2a)

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) tolerates β-lactam antibiotics by carrying out cell wall synthesis with the transpeptidase Penicillin-binding protein 2a (PBP2a), which cannot be inhibited by β-lactams. It has been proposed that PBP2a's active site is protected by two loops to reduce the probability of it binding with β-lactams. Previous crystallographic studies suggested that this protected active site opens for reaction once a native substrate binds at an allosteric domain of PBP2a. This opening was proposed for the new β-lactam ceftaroline's mechanism in successfully treating MRSA infections, i. e. by it binding to the allosteric site, thereby opening the active site to inhibition. In this work, we investigate the binding of ceftaroline at this proposed allosteric site using molecular dynamics simulations. Unstable binding was observed using the major force fields CHARMM36 and Amber ff14SB, and free energy calculations were unable to confirm a strong allosteric effect. Our study suggests that the allosteric effect induced by ceftaroline is weak at best.