Modeling reactivation of the phosphorylated human butyrylcholinesterase by QM(DFTB)/MM calculations

Modeling reactivation of the phosphorylated human butyrylcholinesterase by QM(DFTB)/MM calculations Научная публикация

Журнал

Journal of Theoretical and Computational Chemistry
ISSN: 0219-6336 , E-ISSN: 1793-6888

Вых. Данные

Год: 2015, Том: 14, Номер: 07, Номер статьи : 1550051, Страниц : DOI: 10.1142/s0219633615500510

Авторы

Kulakova Anna ¹ , Lushchekina Sofya ² , Grigorenko Bella ^1,2 , Nemukhin Alexander ^1,2

Организации

1	Lomonosov Moscow State University
2	Emanuel Institute of Biochemical Physics of Russian Academy of Sciences

Human butyrylcholinesterase (BChE) is a bioscavenger that protects the enzyme which is critical for the central nerve system, acetylcholinesterase, from poisoning by organophosphorus agents. Elucidating the details of the hydrolysis reaction mechanism is important to understand how the phosphorylated BChE can be reactivated. Application of the QM(DFTB)/MM(AMBER) method to construct the minimum energy pathways for the hydrolysis reaction of the diethylphosphorylated BChE allowed us to suggest a mechanism of reactivation of the wild-type and the G117H mutated enzyme. Unlike previous approaches assuming that either His438 or His117 serves as a general base in the catalysis, in our proposal the Glu197 residue is responsible for activation of the nucleophilic water molecule (Wat) leading to the chemical transformations that restore the catalytic Ser198 residue in BChE. In agreement with the experimental data, it is shown that the G117H mutation facilitates the reactivation of the inhibited enzyme.

Kulakova A. , Lushchekina S. , Grigorenko B. , Nemukhin A.
Modeling reactivation of the phosphorylated human butyrylcholinesterase by QM(DFTB)/MM calculations
Journal of Theoretical and Computational Chemistry. 2015. V.14. N07. 1550051 . DOI: 10.1142/s0219633615500510 Scopus OpenAlex

Scopus:	2-s2.0-84949533946
OpenAlex:	W1846513719

БД	Цитирований
OpenAlex	14