The catalytic role of water in the binding site of L,D-transpeptidase 2 within acylation mechanism: A QM/MM (ONIOM) modelling

Collins U. Ibeji, Gideon F. Tolufashe, Thandokuhle Ntombela, Thavendran Govender, Glenn E.M. Maguire, Gyanu Lamichhane, Hendrik G. Kruger, Bahareh Honarparvar

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Mycobacterium tuberculosis is the causative agent of Tuberculosis. Formation of 3 → 3 crosslinks in the peptidoglycan layer of M. tuberculosis is catalyzed by L,D-transpeptidases. These enzymes can confer resistance against classical β-lactams that inhibit enzymes that generate 4 → 3 peptidoglycan crosslinks. The focus of this study is to investigate the catalytic role of water molecules in the acylation mechanism of the β-lactam ring within two models; 4- and 6-membered ring systems using two-layered our Own N-layer integrated Molecular Mechanics ONIOM (B3LYP/6-311++G(2d,2p): AMBER) model. The obtained thermochemical parameters revealed that the 6-membered ring model best describes the inhibition mechanism of acylation which indicates the role of water in the preference of 6-membered ring reaction pathway. This finding is in accordance with experimental data for the rate-limiting step of cysteine protease with the same class of inhibitor and binding affinity for both inhibitors. As expected, the ΔG # results also reveal that the 6-membered ring reaction pathway is the most favourable. The electrostatic potential (ESP) and the natural bond orbital analysis (NBO) showed stronger interactions in 6-membered ring transition state (TS-6) mechanism involving water in the active site of the enzyme. This study could be helpful in the development of novel antibiotics against L,D-transpeptidase.

Original languageEnglish (US)
Pages (from-to)222-230
Number of pages9
StatePublished - Dec 2018


  • Carbapenem
  • L,D-transpeptidases
  • Own N-Layer integrated molecular mechanics (ONIOM)
  • Quantum mechanics/molecular mechanics (QM/MM)
  • Transition state (TS)

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases


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