Biochemistry, volume 53, issue 45, pages 7093-7099

Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate

Khrenova Maria G. ¹

Mironov Vladimir ¹

Grigorenko Bella ^{1, 2}

Nemukhin Alexander ^{1, 2}

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Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russian Federation |

N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Kosygina 4, Moscow 119334, Russian Federation |

Publication type: Journal Article

Publication date: 2014-11-04

American Chemical Society (ACS)

Journal: Biochemistry

Quartile SCImago

Quartile WOS

Impact factor: 2.9

ISSN: 00062960, 15204995

DOI: 10.1021/bi5011333

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Biochemistry

Abstract

Cancer-associated point mutations in Ras, in particular, at glycine 12 and glycine 13, 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 (Protein Data Bank entry 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 wild-type Ras, the conformations fluctuated near the structure ready to be involved in the efficient chemical reaction 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, which 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 in the reaction rate. The obtained computational results correlate well with the recent kinetic measurements of the Ras-GAP-catalyzed hydrolysis of GTP.

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Khrenova M. G. et al. Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate // Biochemistry. 2014. Vol. 53. No. 45. pp. 7093-7099.

GOST all authors (up to 50) Copy

Khrenova M. G., Mironov V., Grigorenko B., Nemukhin A. Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate // Biochemistry. 2014. Vol. 53. No. 45. pp. 7093-7099.

RIS |

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RIS Copy

TY - JOUR

DO - 10.1021/bi5011333

UR - https://doi.org/10.1021%2Fbi5011333

TI - Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate

T2 - Biochemistry

AU - Khrenova, Maria G.

AU - Mironov, Vladimir

AU - Grigorenko, Bella

AU - Nemukhin, Alexander

PY - 2014

DA - 2014/11/04 00:00:00

PB - American Chemical Society (ACS)

SP - 7093-7099

IS - 45

VL - 53

SN - 0006-2960

SN - 1520-4995

ER -

BibTex |

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@article{2014_Khrenova,

author = {Maria G. Khrenova and Vladimir Mironov and Bella Grigorenko and Alexander Nemukhin},

title = {Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate},

journal = {Biochemistry},

year = {2014},

volume = {53},

publisher = {American Chemical Society (ACS)},

month = {nov},

url = {https://doi.org/10.1021%2Fbi5011333},

number = {45},

pages = {7093--7099},

doi = {10.1021/bi5011333}

}

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Khrenova, Maria G., et al. “Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate.” Biochemistry, vol. 53, no. 45, Nov. 2014, pp. 7093-7099. https://doi.org/10.1021%2Fbi5011333.

Found error?

Publisher

American Chemical Society (ACS)

Journal

Biochemistry

Quartile SCImago

Quartile WOS

Impact factor

2.9

ISSN

00062960 (Print)
15204995 (Electronic)

Labs

Laboratory of Quantum Chemistry and Molecular Modeling

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