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Molecular dynamics simulations of Gly-12-->Val mutant of p21(ras): dynamic inhibition mechanism
1Computational Science Division, Institute of Physical and Chemical Research, Wako-shi, Saitama 351-0198, Japan. foota@gsc.riken.go.jp
Abstract:
The mutant p21(ras) protein is a G protein produced by the point-mutated H-ras gene, and this mutant protein has been shown to cause carcinogenesis due to a reduction in its GTPase activity. However, the mechanism underlying this strange phenomenon has still not been elucidated. In our previous study, we have clarified the mechanism of the GTP-->GDP hydrolysis reaction in the wild-type p21(ras) at the atomic level and concluded that GTPase-activating protein plays a significant role in the supply of H2O molecules for the hydrolysis. The structure of the active site in the mutant is the same as that in the wild type. However, by performing molecular dynamic calculations, we found that the structure of the active site of the enzyme substrate complex in the oncogenic mutant p21(ras) continuously changes, and these continuous changes in the active site would make it difficult for the GTP-->GDP hydrolysis reaction to occur in the mutant. These findings can explain the fact that the GTPase activity in the mutant was only 15% of that in the wild type and the fact that GTPase-activating protein has no reaction-activating effect in the mutant. This is a dynamic inhibition mechanism of a vital reaction that can be explained by considering the molecular dynamics.
Insights
Mutant p21(ras) proteins, linked to cancer, exhibit reduced GTPase activity due to dynamic active site changes. This molecular instability hinders GTP hydrolysis, explaining reduced function in oncogenic H-ras mutations.
Area of Science:
- Molecular Biology
- Biochemistry
- Oncology
Background:
- Mutant p21(ras) proteins, arising from H-ras gene mutations, are implicated in carcinogenesis.
- Reduced GTPase activity of mutant p21(ras) is a known factor in cancer development, but the underlying mechanism remains unclear.
- Previous research elucidated the GTP-GTP hydrolysis mechanism in wild-type p21(ras), highlighting the role of GTPase-activating protein in supplying water molecules.
Purpose of the Study:
- To elucidate the mechanism behind the reduced GTPase activity in oncogenic p21(ras) mutants.
- To investigate the structural dynamics of the active site in mutant p21(ras) and their impact on GTP hydrolysis.
- To explain why GTPase-activating protein is ineffective in promoting hydrolysis in the mutant form.
Main Methods:
- Molecular dynamics (MD) calculations were employed to analyze the enzyme-substrate complex of the oncogenic p21(ras) mutant.
- Comparison of active site structures between wild-type and mutant p21(ras) proteins.
- Analysis of GTP-->GDP hydrolysis reaction dynamics at the atomic level.
Main Results:
- While the active site structure of the mutant p21(ras) is similar to the wild type, MD simulations revealed continuous structural changes in the mutant's active site.
- These dynamic structural fluctuations impede the GTP-->GDP hydrolysis reaction in the mutant.
- The GTPase activity of the mutant was found to be only 15% of the wild-type activity, and GTPase-activating protein showed no significant activating effect.
Conclusions:
- The reduced GTPase activity in oncogenic p21(ras) mutants is attributed to a dynamic inhibition mechanism.
- Continuous changes in the active site's molecular dynamics hinder the essential GTP hydrolysis reaction.
- Understanding this dynamic inhibition mechanism provides insight into H-ras-driven carcinogenesis.
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