Revealing electronic features governing hydrolysis of cephalosporins in the active site of the L1 metallo-β-lactamase

Levina, E.O.; Khrenova, M.G.; Astakhov, A.A.; Tsirelson, V.G.

Авторы: Levina E.O., Khrenova M.G., Astakhov A.A., Tsirelson V.G.
Журнал: RSC advances
Том: 10
Год издания: 2020
Издательство: Royal Society of Chemistry
Местоположение издательства: United Kingdom
Первая страница: 8664
Последняя страница: 8676
DOI: 10.1039/c9ra10649a
Аннотация: The QM/MM simulations followed by electron density feature analysis are carried out to deepen theunderstanding of the reaction mechanism of cephalosporin hydrolysis in the active site of the L1metallo-b-lactamase. The differences in reactivity of ten similar cephalosporin compounds are explainedby using an extended set of bonding descriptors. The limiting step of the reaction is characterized by theproton transfer to the nitrogen atom of the cephalosporin thiazine ring accompanied with formation ofthe C4]C3 double bond in its N–C4–C3 fragment. The temporary N/H–Ow hydrogen bond, which isformed in the transition state of the limiting step of the reaction was recognized as a key atomicinteraction governing the reactivity of various cephalosporins. Non-local real-space bonding descriptorsshow that different extent of localization of electron lone pair at N atom in the transition state affect thereactivity of compounds: smaller electron localization is typical for the less reactive species. In particular,the Fermi hole analysis shows how exchange electron correlation in the N/H–Ow fragment controlelectron lone pair localization. Delocalization tensor, linear response kernel and source function indicatethat features of electron delocalization in the N–C4–C3 fragment of cephalosporins in the transitionstate complexes determine the differences in C4–C3 bond for substrates with high and low rateconstants. The C4–C3 bond of the N–C4–C3 fragment at the transition state is similar to that of thepreceding intermediate for the less reactive species and resembles the features of the enzyme–productcomplex for more reactive compounds. The power and limitations of the descriptors applied for solvingthe problem are discussed and the generality of approach is stressed.
Добавил в систему: Цирельсон Владимир Григорьевич

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Revealing electronic features governing hydrolysis of cephalosporins in the active site of the L1 metallo-β-lactamaseстатья

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