Journal
NEW JOURNAL OF CHEMISTRY
Volume 43, Issue 19, Pages 7329-7338Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c9nj00254e
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Funding
- Russian Science Foundation [18-74-10056]
- Lomonosov Moscow State University [RFMEFI62117X0011]
- Russian Science Foundation [18-74-10056] Funding Source: Russian Science Foundation
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We developed relationships between the calculated microscopic parameters in the active site of L1 metallo--lactamase and the experimentally observed catalytic rate constants k(cat) of hydrolysis of cephalosporin compounds. The atomic interactions are quantified using various QTAIM bond descriptors in the active sites of 10 protein-antibiotic complexes obtained at the QM/MM level in the transition states of the limiting stage. We identify key atomic interactions that are mainly responsible for the macroscopic properties and reveal that the NsH hydrogen bond determines the catalytic rate constants in cephalosporin-L1 metallo--lactamase systems. The best descriptor for this interaction is the contribution of the N-s atom to the electron density at the hydrogen bond critical point, which was established using the source function for the electron density. The estimated rate constant for ceftazidime, which was not included in the training set, is 15.7 +/- 3.9 s(-1),which reproduces the experimental k(cat) value of 15.4 s(-1). Also, we propose a fluorinated derivative of cefoxitin that demonstrates the lowest rate constant among the known cephalosporin compounds. We suppose that our concept is transferable for other enzymatic reactions.
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