Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas Protein
We report the results of computational studies of the guanosine triphosphate (GTP) hydrolysis in the active site of the KRas-NF1 protein complex, where KRas stands for the K-isoform of the Ras (ras sarcoma) protein and NF1 (neurofbromin-1) is the activating protein. The model system was constructed...
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MDPI AG
2023-05-01
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| Series: | Biophysica |
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| Online Access: | https://www.mdpi.com/2673-4125/3/2/25 |
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| author | Igor Polyakov Alexander Nemukhin |
| author_facet | Igor Polyakov Alexander Nemukhin |
| author_sort | Igor Polyakov |
| collection | DOAJ |
| description | We report the results of computational studies of the guanosine triphosphate (GTP) hydrolysis in the active site of the KRas-NF1 protein complex, where KRas stands for the K-isoform of the Ras (ras sarcoma) protein and NF1 (neurofbromin-1) is the activating protein. The model system was constructed using coordinates of heavy atoms from the crystal structure PDB ID 6OB2 with the GTP analog GMPPNP. Large-scale classical molecular dynamics (MD) calculations were performed to analyze conformations of the enzyme-substrate complexes. The Gibbs energy profiles for the hydrolysis reaction were computed using MD simulations with quantum mechanics/molecular mechanics (QM/MM) interaction potentials. The density functional theory DFT(ωB97X-D3/6-31G**) approach was applied in QM and the CHARMM36 force field parameters in MM. The most likely scenario of the chemical step of the GTP hydrolysis in KRas-NF1 corresponds to the water-assisted mechanism of the formation of the inorganic phosphate coupled with the dissociation of GTP to GDP. |
| first_indexed | 2024-03-11T02:42:04Z |
| format | Article |
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| language | English |
| last_indexed | 2024-03-11T02:42:04Z |
| publishDate | 2023-05-01 |
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| spelling | doaj.art-b2bfe1cffce24230bf2b46465014951a2023-11-18T09:32:07ZengMDPI AGBiophysica2673-41252023-05-013237338410.3390/biophysica3020025Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas ProteinIgor Polyakov0Alexander Nemukhin1Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119991, RussiaDepartment of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119991, RussiaWe report the results of computational studies of the guanosine triphosphate (GTP) hydrolysis in the active site of the KRas-NF1 protein complex, where KRas stands for the K-isoform of the Ras (ras sarcoma) protein and NF1 (neurofbromin-1) is the activating protein. The model system was constructed using coordinates of heavy atoms from the crystal structure PDB ID 6OB2 with the GTP analog GMPPNP. Large-scale classical molecular dynamics (MD) calculations were performed to analyze conformations of the enzyme-substrate complexes. The Gibbs energy profiles for the hydrolysis reaction were computed using MD simulations with quantum mechanics/molecular mechanics (QM/MM) interaction potentials. The density functional theory DFT(ωB97X-D3/6-31G**) approach was applied in QM and the CHARMM36 force field parameters in MM. The most likely scenario of the chemical step of the GTP hydrolysis in KRas-NF1 corresponds to the water-assisted mechanism of the formation of the inorganic phosphate coupled with the dissociation of GTP to GDP.https://www.mdpi.com/2673-4125/3/2/25KRas proteinGTP hydrolysisactivating protein GAPreaction mechanismGibbs energy profilesmolecular dynamics |
| spellingShingle | Igor Polyakov Alexander Nemukhin Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas Protein Biophysica KRas protein GTP hydrolysis activating protein GAP reaction mechanism Gibbs energy profiles molecular dynamics |
| title | Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas Protein |
| title_full | Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas Protein |
| title_fullStr | Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas Protein |
| title_full_unstemmed | Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas Protein |
| title_short | Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas Protein |
| title_sort | computational modeling of the neurofibromin stimulated guanosine triphosphate hydrolysis by the kras protein |
| topic | KRas protein GTP hydrolysis activating protein GAP reaction mechanism Gibbs energy profiles molecular dynamics |
| url | https://www.mdpi.com/2673-4125/3/2/25 |
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