Molecular Dynamics Study of the Complex Formation of TEM-Type β-Lactamases with Substrates and Inhibitors


Citar

Texto integral

Acesso aberto Acesso aberto
Acesso é fechado Acesso está concedido
Acesso é fechado Somente assinantes

Resumo

The complex formation of TEM-1 β-lactamase and its three mutant forms TEM-32, TEM-37, and TEM-39 with substrates cephalothin and CENTA and serine beta-lactamase inhibitors sulbactam, tazobactam, and clavulanic acid is studied using the methods of molecular dynamics. It is found that the stability of the complexes is caused by the electrostatic attraction between the deprotonated carboxyl group of the β-lactam ring of the substrate (inhibitor) and the positively charged amino groups of the lysine 234 and 73 residues, located in the active site of the enzymes. The formation of a hydrogen bond between this substrate group or its carbonyl oxygen with the hydroxyl group of the catalytic serine 70 residue and also between the negatively charged substituent groups and the positive charge region formed by the arginine 244 guanidine group and the asparagine 276 amino group is observed for some complexes. The binding energy of CENTA with TEM-1 β-lactamase is below the analogous binding energy of cephalothin, which is confirmed by the values of the Michaelis constants, determined experimentally. It is also found that the inhibitors bind to the mutant forms of β-lactamases related to the inhibitor-resistant phenotype, with higher affinity than TEM-1 β-lactamase.

Sobre autores

I. Uporov

Department of Chemistry

Email: mrubtsova@gmail.com
Rússia, Moscow, 119991

V. Grigorenko

Email: mrubtsova@gmail.com

M. Rubtsova

Department of Chemistry

Autor responsável pela correspondência
Email: mrubtsova@gmail.com
Rússia, Moscow, 119991

A. Egorov

Department of Chemistry

Email: mrubtsova@gmail.com
Rússia, Moscow, 119991

Arquivos suplementares

Arquivos suplementares
Ação
1. JATS XML

Declaração de direitos autorais © Allerton Press, Inc., 2018