QM/MM investigation of substrate binding of subclass B3 metallo-β-lactamase SMB-1 from Serratia marcescents: insights into catalytic mechanism

Journal of Molecular Modeling
Xia Mu, Dingguo Xu

Abstract

Metallo-β-lactamases (MβLs) can hydrolyze and deactivate lactam-containing antibiotics, which are the major mechanism to cause drug resistance in the treatment of bacterial infections. This has become a global concern due to the lack of clinically approved inhibitors so far. SMB-1 from Serratia marcescents is a novel B3 subclass MβL, which could inactivate nearly all β-lactam-containing antibiotics, e.g., cephalosporins and carbapenems. It represents a new round of worrisome bacterial resistance. In this work, the Michaelis model of SMB-1 in complex with ampicillin was simulated using combined quantum mechanical and molecular mechanical method. Similar with other dizinc MβLs, a Zn-bridged hydroxide ion was simulated as the nucleophile for the hydrolysis reaction assisted by D120. The protonation of D120 could lead to the loss of Oδ2-Zn2 coordination bond, whereas the C3 carboxylate group moves down to become a new ligand to Zn2. The initial β-lactam ring-opening reaction leads to a conserved nitrogen anionic intermediate, which forms a new ligation between the resulted nitrogen anion and Zn2. The corresponding reaction free energy barrier for the first step of lactam ring-opening reaction was calculated to be 19.2 kcal/mol. Dur...Continue Reading

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