TY - JOUR
T1 - The catalytic role of water in the binding site of L,D-transpeptidase 2 within acylation mechanism
T2 - A QM/MM (ONIOM) modelling
AU - Ibeji, Collins U.
AU - Tolufashe, Gideon F.
AU - Ntombela, Thandokuhle
AU - Govender, Thavendran
AU - Maguire, Glenn E.M.
AU - Lamichhane, Gyanu
AU - Kruger, Hendrik G.
AU - Honarparvar, Bahareh
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
KW - Carbapenem
KW - L,D-transpeptidases
KW - Own N-Layer integrated molecular mechanics (ONIOM)
KW - Quantum mechanics/molecular mechanics (QM/MM)
KW - Transition state (TS)
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U2 - 10.1016/j.tube.2018.10.005
DO - 10.1016/j.tube.2018.10.005
M3 - Article
C2 - 30514506
AN - SCOPUS:85055889853
VL - 113
SP - 222
EP - 230
JO - Tuberculosis
JF - Tuberculosis
SN - 1472-9792
ER -