The catalytic role of water in the binding site of l,d-transpeptidase 2 within acylation mechanism: A QM/MM (ONIOM) modelling.
Tuberculosis (Edinb)
; 113: 222-230, 2018 12.
Article
in En
| MEDLINE
| ID: mdl-30514506
ABSTRACT
Mycobacterium tuberculosis is the causative agent of Tuberculosis. Formation of 3â¯ââ¯3 crosslinks in the peptidoglycan layer of M. tuberculosis is catalyzed by l,d-transpeptidases. These enzymes can confer resistance against classical ß-lactams that inhibit enzymes that generate 4â¯ââ¯3 peptidoglycan crosslinks. The focus of this study is to investigate the catalytic role of water molecules in the acylation mechanism of the ß-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Bacterial Proteins
/
Water
/
Peptidoglycan
/
Models, Molecular
/
Peptidyl Transferases
/
Mycobacterium tuberculosis
Type of study:
Prognostic_studies
Language:
En
Journal:
Tuberculosis (Edinb)
Year:
2018
Document type:
Article
Affiliation country: