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Modeling the role of G12V and G13V Ras mutations in the RasGAP-catalyzed hydrolysis reaction of guanosine triphosphateстатья
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 15 января 2015 г.
- Авторы: Khrenova Maria G., Mironov Vladimir A., Grigorenko Bella L., Nemukhin Alexander V.
- Журнал: Biochemistry
- Том: 53
- Номер: 45
- Год издания: 2014
- Издательство: American Chemical Society
- Местоположение издательства: United States
- Первая страница: 7093
- Последняя страница: 7099
- DOI: 10.1021/bi5011333
- Аннотация: Cancer associated point mutations in Ras, in particular, at glycine-12 and glycine-13 positions, affect the normal cycle between inactive GDP-bound and active GTP-bound states. In this work, the role of G12V and G13V replacements in the GAP-stimulated intrinsic GTP hydrolysis reaction in Ras is studied using molecular dynamics (MD) simulations with quantum mechanics- molecular mechanics (QM/MM) potentials. A model molecular system was constructed by motifs of the relevant crystal structure (PDBid 1WQ1). QM/MM optimization of geometry parameters in the Ras-GAP-GTP complex and QM/MM-MD simulations were performed with a quantum subsystem comprising a large fraction of the enzyme active site. For the system with the wild-type Ras, the conformations fluctuated near the structure responsible for efficient chemical transformations leading to the cleavage of the phosphorus-oxygen bond in GTP upon approach of the properly aligned catalytic water molecule. Dynamics of the system with the G13V mutant is characterized by an enhanced flexibility in the area occupied by the γ-phosphate group of GTP, catalytic water and the side chains of Arg789 and Gln61, that should somewhat hinder fast chemical steps. Conformational dynamics of the system with the G12V mutant shows considerable displacement of the Gln61 side chain and catalytic water from their favorable arrangement in the active site that may lead to a marked reduction of the reaction rate. The obtained computational results correlate well with the recent kinetics measurements of the Ras-GAP catalyzed hydrolysis of GTP.
- Добавил в систему: Хренова Мария Григорьевна