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Research Article

The switch states of the GDP-bound HRAS affected by point mutations: a study from Gaussian accelerated molecular dynamics simulations and free energy landscapes

, , & ORCID Icon
Pages 3363-3381 | Received 23 Feb 2023, Accepted 04 May 2023, Published online: 22 May 2023

References

  • Ahmadian, M. R., Zor, T., Vogt, D., Kabsch, W., Selinger, Z., Wittinghofer, A., & Scheffzek, K. (1999). Guanosine triphosphatase stimulation of oncogenic Ras mutants. Proceedings of the National Academy of Sciences of the United States of America, 96(12), 7065–7070. https://doi.org/10.1073/pnas.96.12.7065
  • Akher, F. B., Farrokhzadeh, A., Ravenscroft, N., & Kuttel, M. M. (2022). Deciphering the mechanism of binding selectivity of chlorofluoroacetamide-based covalent inhibitors toward L858R/T790M resistance mutation. Journal of Chemical Information and Modeling, 62(4), 997–1013. https://doi.org/10.1021/acs.jcim.1c01399
  • Amadei, A., Linssen, A. B. M., & Berendsen, H. J. C. (1993). Essential dynamics of proteins. Proteins, 17(4), 412–425. https://doi.org/10.1002/prot.340170408
  • An, X., Bai, Q., Bing, Z., Liu, H., Zhang, Q., Liu, H., & Yao, X. (2020). Revealing the positive binding cooperativity mechanism between the orthosteric and the allosteric antagonists of CCR2 by metadynamics and gaussian accelerated molecular dynamics simulations. ACS Chemical Neuroscience, 11(4), 628–637. https://doi.org/10.1021/acschemneuro.9b00630
  • Anandakrishnan, R., Aguilar, B., & Onufriev, A. V. (2012). H++ 3.0: Automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations. Nucleic Acids Research, 40, W537–W541. https://doi.org/10.1093/nar/gks375
  • Bandaru, P., Shah, N. H., Bhattacharyya, M., Barton, J. P., Kondo, Y., Cofsky, J. C., Gee, C. L., Chakraborty, A. K., Kortemme, T., Ranganathan, R., & Kuriyan, J. (2017). Deconstruction of the Ras switching cycle through saturation mutagenesis. eLife, 6, e27810. https://doi.org/10.7554/eLife.27810
  • Bao, H., Wang, W., Sun, H., & Chen, J. (2023a). Probing mutation-induced conformational transformation of the GTP/M-RAS complex through Gaussian accelerated molecular dynamics simulations. Journal of Enzyme Inhibition and Medicinal Chemistry, 38(1), 2195995. https://doi.org/10.1080/14756366.14752023.12195995
  • Bao, H. Y., Wang, W., Sun, H. B., & Chen, J. Z. (2023b). Binding modes of GDP, GTP and GNP to NRAS deciphered by using Gaussian accelerated molecular dynamics simulations. SAR and QSAR in Environmental Research, 34(1), 65–89. https://doi.org/10.1080/1062936X.2023.2165542
  • Bièche, I., Coussy, F., El-Botty, R., Vacher, S., Château-Joubert, S., Dahmani, A., Montaudon, E., Reyes, C., Gentien, D., Reyal, F., Ricci, F., Nicolas, A., Marchio, C., Vincent-Salomon, A., Laé, M., & Marangoni, E. (2021). HRAS is a therapeutic target in malignant chemo-resistant adenomyoepithelioma of the breast. Journal of Hematology & Oncology, 14(1), 143. https://doi.org/10.1186/s13045-021-01158-3
  • Boriack-Sjodin, P. A., Margarit, S. M., Bar-Sagi, D., & Kuriyan, J. (1998). The structural basis of the activation of Ras by Sos. Nature, 394(6691), 337–343. https://doi.org/10.1038/28548
  • Bourne, H. R., Sanders, D. A., & McCormick, F. (1990). The GTPase superfamily: A conserved switch for diverse cell functions. Nature, 348(6297), 125–132. https://doi.org/10.1038/348125a0
  • Braka, A., Garnier, N., Bonnet, P., & Aci-Sèche, S. (2020). Residence time prediction of type 1 and 2 kinase inhibitors from unbinding simulations. Journal of Chemical Information and Modeling, 60(1), 342–348. https://doi.org/10.1021/acs.jcim.9b00497
  • Buhrman, G., Holzapfel, G., Fetics, S., & Mattos, C. (2010). Allosteric modulation of Ras positions Q61 for a direct role in catalysis. Proceedings of the National Academy of Sciences of the United States of America, 107(11), 4931–4936. https://doi.org/10.1073/pnas.0912226107
  • Bunda, S., Heir, P., Srikumar, T., Cook, J. D., Burrell, K., Kano, Y., Lee, J. E., Zadeh, G., Raught, B., & Ohh, M. (2014). Src promotes GTPase activity of Ras via tyrosine 32 phosphorylation. Proceedings of the National Academy of Sciences of the United States of America, 111(36), E3785–E3794. https://doi.org/10.1073/pnas.1406559111
  • Case, D. A., Belfon, K., Ben-Shalom, I. Y., Brozell, S. R., Cerutti, D. S., Cheatham, I., T. E. … Kollman, P. A. (2020). AMBER 2020. University of California.
  • Case, D. A., Cheatham, T. E., Darden, T., Gohlke, H., Luo, R., Merz, K. M., Onufriev, A., Simmerling, C., Wang, B., & Woods, R. J. (2005). The Amber biomolecular simulation programs. Journal of Computational Chemistry, 26(16), 1668–1688. https://doi.org/10.1002/jcc.20290
  • Chen, J., Wang, L., Wang, W., Sun, H., Pang, L., & Bao, H. (2021a). Conformational transformation of switch domains in GDP/K-Ras induced by G13 mutants: An investigation through Gaussian accelerated molecular dynamics simulations and principal component analysis. Computers in Biology and Medicine, 135, 104639. https://doi.org/10.1016/j.compbiomed.2021.104639
  • Chen, J., Wang, W., Pang, L., & Zhu, W. (2020). Unveiling conformational dynamics changes of H-Ras induced by mutations based on accelerated molecular dynamics. Physical Chemistry Chemical Physics, 22(37), 21238–21250. https://doi.org/10.1039/D0CP03766D
  • Chen, J., Zeng, Q., Wang, W., Sun, H., & Hu, G. (2022a). Decoding the identification mechanism of an SAM-III Riboswitch on ligands through multiple independent Gaussian-accelerated molecular dynamics simulations. Journal of Chemical Information and Modeling, 62(23), 6118–6132. https://doi.org/10.1021/acs.jcim.1022c00961
  • Chen, J., Zhang, S., Wang, W., Pang, L., Zhang, Q., & Liu, X. (2021b). Mutation-induced impacts on the switch transformations of the GDP- and GTP-bound K-Ras: Insights from multiple replica gaussian accelerated molecular dynamics and free energy analysis. Journal of Chemical Information and Modeling, 61(4), 1954–1969. https://doi.org/10.1021/acs.jcim.0c01470
  • Chen, J., Zhang, S., Zeng, Q., Wang, W., Zhang, Q., & Liu, X. (2022b). Free energy profiles relating with conformational transition of the switch domains induced by G12 mutations in GTP-bound KRAS. Frontiers in Molecular Biosciences, 9, 912518. https://doi.org/10.3389/fmolb.2022.912518
  • Clausen, R., Ma, B., Nussinov, R., & Shehu, A. (2015). Mapping the conformation space of wildtype and mutant H-Ras with a memetic, cellular, and multiscale evolutionary algorithm. PLoS Computational Biology, 11(9), e1004470. https://doi.org/10.1371/journal.pcbi.1004470
  • Corbett, K. D., & Alber, T. (2001). The many faces of Ras: Recognition of small GTP-binding proteins. Trends in Biochemical Sciences, 26(12), 710–716. https://doi.org/10.1016/S0968-0004(01)01974-0
  • Cruz-Migoni, A., Canning, P., Quevedo, C. E., Bataille, C. J. R., Bery, N., Miller, A., Russell, A. J., Phillips, S. E. V., Carr, S. B., & Rabbitts, T. H. (2019). Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds. Proceedings of the National Academy of Sciences of the United States of America, 116(7), 2545–2550. https://doi.org/10.1073/pnas.1811360116
  • Essmann, U., Perera, L., Berkowitz, M. L., Darden, T., Lee, H., & Pedersen, L. G. (1995). A smooth particle mesh Ewald method. The Journal of Chemical Physics, 103(19), 8577–8593. https://doi.org/10.1063/1.470117
  • Fetics, S. K., Guterres, H., Kearney, B. M., Buhrman, G., Ma, B., Nussinov, R., & Mattos, C. (2015). Allosteric effects of the oncogenic RasQ61L mutant on Raf-RBD. Structure (London, England: 1993), 23(3), 505–516. https://doi.org/10.1016/j.str.2014.12.017
  • Franken, S. M., Scheidig, A. J., Krengel, U., Rensland, H., Lautwein, A., Geyer, M., Scheffzek, K., Goody, R. S., Kalbitzer, H. R., & Pai, E. F. (1993). Three-dimensional structures and properties of a transforming and a nontransforming glycine-12 mutant of p21H-ras. Biochemistry, 32(33), 8411–8420. https://doi.org/10.1021/bi00084a005
  • Fraser, J. S., van den Bedem, H., Samelson, A. J., Lang, P. T., Holton, J. M., Echols, N., & Alber, T. (2011). Accessing protein conformational ensembles using room-temperature X-ray crystallography. Proceedings of the National Academy of Sciences of the United States of America, 108(39), 16247–16252. https://doi.org/10.1073/pnas.1111325108
  • Götz, A. W., Williamson, M. J., Xu, D., Poole, D., Le Grand, S., & Walker, R. C. (2012). Routine microsecond molecular dynamics simulations with AMBER on GPUs. 1. Generalized born. Journal of Chemical Theory and Computation, 8(5), 1542–1555. https://doi.org/10.1021/ct200909j
  • Gao, Y., Zhu, T., & Chen, J. (2018). Exploring drug-resistant mechanisms of I84V mutation in HIV-1 protease toward different inhibitors by thermodynamics integration and solvated interaction energy method. Chemical Physics Letters, 706, 400–408. https://doi.org/10.1016/j.cplett.2018.06.040
  • Gentile, D. R., Rathinaswamy, M. K., Jenkins, M. L., Moss, S. M., Siempelkamp, B. D., Renslo, A. R., Burke, J. E., & Shokat, K. M. (2017). Ras binder induces a modified switch-II pocket in GTP and GDP states. Cell Chemical Biology, 24(12), 1455–1466.e1414. https://doi.org/10.1016/j.chembiol.2017.08.025
  • Geyer, M., Schweins, T., Herrmann, C., Prisner, T., Wittinghofer, A., & Kalbitzer, H. R. (1996). Conformational transitions in p21ras and in its complexes with the effector protein Raf-RBD and the GTPase activating protein GAP. Biochemistry, 35(32), 10308–10320. https://doi.org/10.1021/bi952858k
  • Ghosh, R., Chakraborty, A., Biswas, A., & Chowdhuri, S. (2022a). Computer aided identification of potential SARS CoV-2 main protease inhibitors from diterpenoids and biflavonoids of Torreya nucifera leaves. Journal of Biomolecular Structure & Dynamics, 40(6), 2647–2662. https://doi.org/10.1080/07391102.2020.1841680
  • Ghosh, R., Chakraborty, A., Biswas, A., & Chowdhuri, S. (2022b). Depicting the inhibitory potential of polyphenols from Isatis indigotica root against the main protease of SARS CoV-2 using computational approaches. Journal of Biomolecular Structure & Dynamics, 40(9), 4110–4121. https://doi.org/10.1080/07391102.2020.1858164
  • Girard, E., Lopes, P., Spoerner, M., Dhaussy, A.-C., Prangé, T., Kalbitzer, H. R., & Colloc’h, N. (2022). Equilibria between conformational states of the Ras oncogene protein revealed by high pressure crystallography. Chemical Science, 13(7), 2001–2010. https://doi.org/10.1039/D1SC05488K
  • Grant, B. J., Gorfe, A., & McCammon, J. A. (2009). Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics. PLoS Computational Biology, 5(3), e1000325. https://doi.org/10.1371/journal.pcbi.1000325
  • Guerra, J. V. d S., Ribeiro-Filho, H. V., Jara, G. E., Bortot, L. O., Pereira, J. G. d C., & Lopes-de-Oliveira, P. S. (2021). pyKVFinder: An efficient and integrable Python package for biomolecular cavity detection and characterization in data science. BMC Bioinformatics, 22(1), 607. https://doi.org/10.1186/s12859-021-04519-4
  • Guerra, J. V. d S., Ribeiro Filho, H. V., Bortot, L. O., Honorato, R. V., Pereira, J. G. d C., & Lopes-de-Oliveira, P. S. (2020). ParKVFinder: A thread-level parallel approach in biomolecular cavity detection. SoftwareX, 12, 100606. https://doi.org/10.1016/j.softx.2020.100606
  • Hall, A., & Self, A. J. (1986). The effect of Mg2+ on the guanine nucleotide exchange rate of p21N-ras. The Journal of Biological Chemistry, 261(24), 10963–10965. https://doi.org/10.1016/S0021-9258(18)67333-8
  • Henzler-Wildman, K., & Kern, D. (2007). Dynamic personalities of proteins. Nature, 450(7172), 964–972. https://doi.org/10.1038/nature06522
  • Hong, L., & Sklar, L. A. (2014). Targeting GTPases in Parkinson’s disease: Comparison to the historic path of kinase drug discovery and perspectives. Frontiers in Molecular Neuroscience, 7, 52. https://doi.org/10.3389/fnmol.2014.00052
  • Hou, T., & Yu, R. (2007). Molecular dynamics and free energy studies on the wild-type and double mutant HIV-1 protease complexed with amprenavir and two amprenavir-related inhibitors: Mechanism for binding and drug resistance. Journal of Medicinal Chemistry, 50(6), 1177–1188. https://doi.org/10.1021/jm0609162
  • Hu, Z., & Marti, J. (2022). Discovering and targeting dynamic drugging pockets of oncogenic proteins: The role of magnesium in conformational changes of the G12D mutated Kirsten rat sarcoma-guanosine diphosphate complex. International Journal of Molecular Sciences, 23(22), 13865. https://doi.org/10.3390/ijms232213865
  • Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD: Visual molecular dynamics. Journal of Molecular Graphics, 14(1), 33–38. https://doi.org/10.1016/0263-7855(96)00018-5
  • Ichiye, T., & Karplus, M. (1991). Collective motions in proteins: A covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations. Proteins, 11(3), 205–217. https://doi.org/10.1002/prot.340110305
  • Ito, Y., Yamasaki, K., Iwahara, J., Terada, T., Kamiya, A., Shirouzu, M., Muto, Y., Kawai, G., Yokoyama, S., Laue, E. D., Wälchli, M., Shibata, T., Nishimura, S., & Miyazawa, T. (1997). Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein. Biochemistry, 36(30), 9109–9119. https://doi.org/10.1021/bi970296u
  • Izaguirre, J. A., Catarello, D. P., Wozniak, J. M., & Skeel, R. D. (2001). Langevin stabilization of molecular dynamics. The Journal of Chemical Physics, 114(5), 2090–2098. https://doi.org/10.1063/1.1332996
  • Jakalian, A., Bush, B. L., Jack, D. B., & Bayly, C. I. (2000). Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method. Journal of Computational Chemistry, 21(2), 132–146. https://doi.org/10.1002/(SICI)1096-987X(20000130)21:2<132::AID-JCC5>3.0.CO;2-P
  • Jakalian, A., Jack, D. B., & Bayly, C. I. (2002). Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation. Journal of Computational Chemistry, 23(16), 1623–1641. https://doi.org/10.1002/jcc.10128
  • Johnson, C. W., Lin, Y.-J., Reid, D., Parker, J., Pavlopoulos, S., Dischinger, P., Graveel, C., Aguirre, A. J., Steensma, M., Haigis, K. M., & Mattos, C. (2019). Isoform-specific destabilization of the active site reveals a molecular mechanism of intrinsic activation of KRas G13D. Cell Reports, 28(6), 1538–1550.e1537. https://doi.org/10.1016/j.celrep.2019.07.026
  • Johnson, C. W., Seo, H.-S., Terrell, E. M., Yang, M.-H., KleinJan, F., Gebregiworgis, T., Gasmi-Seabrook, G. M. C., Geffken, E. A., Lakhani, J., Song, K., Bashyal, P., Popow, O., Paulo, J. A., Liu, A., Mattos, C., Marshall, C. B., Ikura, M., Morrison, D. K., Dhe-Paganon, S., & Haigis, K. M. (2022). Regulation of GTPase function by autophosphorylation. Molecular Cell, 82(5), 950–968.e914. https://doi.org/10.1016/j.molcel.2022.02.011
  • Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W., & Klein, M. L. (1983). Comparison of simple potential functions for simulating liquid water. The Journal of Chemical Physics, 79(2), 926–935. https://doi.org/10.1063/1.445869
  • Joung, I. S., & Cheatham, T. E. (2008). Determination of alkali and halide monovalent ion parameters for use in explicitly solvated biomolecular simulations. The Journal of Physical Chemistry. B, 112(30), 9020–9041. https://doi.org/10.1021/jp8001614
  • Joung, I. S., & Cheatham, T. E. (2009). Molecular dynamics simulations of the dynamic and energetic properties of alkali and halide ions using water-model-specific ion parameters. The Journal of Physical Chemistry. B, 113(40), 13279–13290. https://doi.org/10.1021/jp902584c
  • Karnoub, A. E., & Weinberg, R. A. (2008). Ras oncogenes: Split personalities. Nature Reviews. Molecular Cell Biology, 9(7), 517–531. https://doi.org/10.1038/nrm2438
  • Kessler, D., Bergner, A., Böttcher, J., Fischer, G., Döbel, S., Hinkel, M., Müllauer, B., Weiss-Puxbaum, A., & McConnell, D. B. (2020). Drugging all RAS isoforms with one pocket. Future Medicinal Chemistry, 12(21), 1911–1923. https://doi.org/10.4155/fmc-2020-0221
  • Khaled, M., Gorfe, A., & Sayyed-Ahmad, A. (2019). Conformational and dynamical effects of Tyr32 phosphorylation in K-Ras: Molecular dynamics simulation and Markov state models analysis. The Journal of Physical Chemistry. B, 123(36), 7667–7675. https://doi.org/10.1021/acs.jpcb.9b05768
  • Kraulis, P. J., Domaille, P. J., Campbell-Burk, S. L., Van Aken, T., & Laue, E. D. (1994). Solution structure and dynamics of Ras p21.cntdot.GDP Determined by heteronuclear three- and four-dimensional NMR spectroscopy. Biochemistry, 33(12), 3515–3531. https://doi.org/10.1021/bi00178a008
  • Li, M., Liu, X., Zhang, S., Liang, S., Zhang, Q., & Chen, J. (2022a). Deciphering the binding mechanism of inhibitors of the SARS-CoV-2 main protease through multiple replica accelerated molecular dynamics simulations and free energy landscapes. Physical Chemistry Chemical Physics: PCCP, 24(36), 22129–22143. https://doi.org/10.1039/D2CP03446H
  • Li, M., Liu, X., Zhang, S., Sun, J., Zhang, Q., & Chen, J. (2022b). Selective mechanism of inhibitors to two bromodomains of BRD4 revealed by multiple replica molecular dynamics simulations and free energy analyses. Chinese Journal of Chemical Physics, 1–15. https://doi.org/10.1063/1674-0068/cjcp2208126
  • Liang, S., Liu, X., Zhang, S., Li, M., Zhang, Q., & Chen, J. (2022). Binding mechanism of inhibitors to SARS-CoV-2 main protease deciphered by multiple replica molecular dynamics simulations. Physical Chemistry Chemical Physics: PCCP, 24(3), 1743–1759. https://doi.org/10.1039/D1CP04361G
  • Liang, S. S., Liu, X. G., Cui, Y. X., Zhang, S. L., Zhang, Q. G., & Chen, J. Z. (2021). Molecular mechanism concerning conformational changes of CDK2 mediated by binding of inhibitors using molecular dynamics simulations and principal component analysis. SAR and QSAR in Environmental Research, 32(7), 573–594. https://doi.org/10.1080/1062936X.2021.1934896
  • Lu, S., Jang, H., Gu, S., Zhang, J., & Nussinov, R. (2016a). Drugging Ras GTPase: A comprehensive mechanistic and signaling structural view. Chemical Society Reviews, 45(18), 4929–4952. https://doi.org/10.1039/C5CS00911A
  • Lu, S., Jang, H., Muratcioglu, S., Gursoy, A., Keskin, O., Nussinov, R., & Zhang, J. (2016b). Ras conformational ensembles, allostery, and signaling. Chemical Reviews, 116(11), 6607–6665. https://doi.org/10.1021/acs.chemrev.5b00542
  • Lu, S., Ni, D., Wang, C., He, X., Lin, H., Wang, Z., & Zhang, J. (2019). Deactivation pathway of Ras GTPase underlies conformational substates as targets for drug design. ACS Catalysis, 9(8), 7188–7196. https://doi.org/10.1021/acscatal.9b02556
  • Ma, J., & Karplus, M. (1997). Molecular switch in signal transduction: Reaction paths of the conformational changes in ras p21. Proceedings of the National Academy of Sciences of the United States of America, 94(22), 11905–11910. https://doi.org/10.1073/pnas.94.22.11905
  • Maier, J. A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K. E., & Simmerling, C. (2015). ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB. Journal of Chemical Theory and Computation, 11(8), 3696–3713. https://doi.org/10.1021/acs.jctc.5b00255
  • Mathiot, L., Herbreteau, G., Robin, S., Fenat, C., Bennouna, J., Blanquart, C., Denis, M., & Pons-Tostivint, E. (2022). HRAS Q61L mutation as a possible target for non-small cell lung cancer: Case series and review of literature. Current Oncology (Toronto, Ont.), 29(5), 3748–3758. https://doi.org/10.3390/curroncol29050300
  • Miao, Y., Feher, V. A., & McCammon, J. A. (2015). Gaussian accelerated molecular dynamics: Unconstrained enhanced sampling and free energy calculation. Journal of Chemical Theory and Computation, 11(8), 3584–3595. https://doi.org/10.1021/acs.jctc.5b00436
  • Miao, Y., & McCammon, J. A. (2016). Graded activation and free energy landscapes of a muscarinic G-protein-coupled receptor. Proceedings of the National Academy of Sciences of the United States of America, 113(43), 12162–12167. https://doi.org/10.1073/pnas.1614538113
  • Miao, Y., & McCammon, J. A. (2018). Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor. Proceedings of the National Academy of Sciences of the United States of America, 115(12), 3036–3041. https://doi.org/10.1073/pnas.1800756115
  • Miao, Y., Sinko, W., Pierce, L., Bucher, D., Walker, R. C., & McCammon, J. A. (2014). Improved reweighting of accelerated molecular dynamics simulations for free energy calculation. Journal of Chemical Theory and Computation, 10(7), 2677–2689. https://doi.org/10.1021/ct500090q
  • Michael, J. V., Wurtzel, J. G. T., & Goldfinger, L. E. (2016). Inhibition of galectin-1 sensitizes HRAS-driven tumor growth to rapamycin treatment. Anticancer Research, 36(10), 5053–5061. https://doi.org/10.21873/anticanres.11074
  • Mo, S. P., Coulson, J. M., & Prior, I. A. (2018). RAS variant signalling. Biochemical Society Transactions, 46(5), 1325–1332. https://doi.org/10.1042/bst20180173
  • Muraoka, S., Shima, F., Araki, M., Inoue, T., Yoshimoto, A., Ijiri, Y., Seki, N., Tamura, A., Kumasaka, T., Yamamoto, M., & Kataoka, T. (2012). Crystal structures of the state 1 conformations of the GTP-bound H-Ras protein and its oncogenic G12V and Q61L mutants. FEBS Letters, 586(12), 1715–1718. https://doi.org/10.1016/j.febslet.2012.04.058
  • Nassar, N., Horn, G., Herrmann, C. A., Scherer, A., McCormick, F., & Wittinghofer, A. (1995). The 2.2 Å crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with RaplA and a GTP analogue. Nature, 375(6532), 554–560. https://doi.org/10.1038/375554a0
  • Nelson, A. C., Turbyville, T. J., Dharmaiah, S., Rigby, M., Yang, R., Wang, T.-Y., Columbus, J., Stephens, R., Taylor, T., Sciacca, D., Onsongo, G., Sarver, A., Subramanian, S., Nissley, D. V., Simanshu, D. K., & Lou, E. (2020). RAS internal tandem duplication disrupts GTPase-activating protein (GAP) binding to activate oncogenic signaling. The Journal of Biological Chemistry, 295(28), 9335–9348. https://doi.org/10.1074/jbc.RA119.011080
  • Nnadi, C. I., Jenkins, M. L., Gentile, D. R., Bateman, L. A., Zaidman, D., Balius, T. E., Nomura, D. K., Burke, J. E., Shokat, K. M., & London, N. (2018). Novel K-Ras G12C Switch-II covalent binders destabilize ras and accelerate nucleotide exchange. Journal of Chemical Information and Modeling, 58(2), 464–471. https://doi.org/10.1021/acs.jcim.7b00399
  • Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013). K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503(7477), 548–551. https://doi.org/10.1038/nature12796
  • Pálfy, G., Vida, I., & Perczel, A. (2020). 1H, 15N backbone assignment and comparative analysis of the wild type and G12C, G12D, G12V mutants of K-Ras bound to GDP at physiological pH. Biomolecular NMR Assignments, 14(1), 1–7. https://doi.org/10.1007/s12104-019-09909-7
  • Pai, E. F., Krengel, U., Petsko, G. A., Goody, R. S., Kabsch, W., & Wittinghofer, A. (1990). Refined crystal structure of the triphosphate conformation of H-ras p21 at 1.35 A resolution: Implications for the mechanism of GTP hydrolysis. The EMBO Journal, 9(8), 2351–2359. https://doi.org/10.1002/j.1460-2075.1990.tb07409.x
  • Pan, J. Y., & Wessling-Resnick, M. (1998). GEF-mediated GDP/GTP exchange by monomeric GTPases: A regulatory role for Mg2+? BioEssays, 20(6), 516–521. https://doi.org/10.1002/(SICI)1521-1878(199806)20:6<516::AID-BIES11>3.0.CO;2-3
  • Parker, J. A., Volmar, A. Y., Pavlopoulos, S., & Mattos, C. (2018). K-Ras populates conformational states differently from its isoform H-Ras and oncogenic mutant K-RasG12D. Structure (London, England : 1993), 26(6), 810–820.e814. https://doi.org/10.1016/j.str.2018.03.018
  • Pierce, L. C. T., Salomon-Ferrer, R., Augusto, F., de Oliveira, C., McCammon, J. A., & Walker, R. C. (2012). Routine access to millisecond time scale events with accelerated molecular dynamics. Journal of Chemical Theory and Computation, 8(9), 2997–3002. https://doi.org/10.1021/ct300284c
  • Prakash, P., Litwin, D., Liang, H., Sarkar-Banerjee, S., Dolino, D., Zhou, Y., Hancock, J. F., Jayaraman, V., & Gorfe, A. A. (2019). Dynamics of membrane-bound G12V-KRAS from simulations and single-molecule FRET in native nanodiscs. Biophysical Journal, 116(2), 179–183. https://doi.org/10.1016/j.bpj.2018.12.011
  • Roe, D. R., & Cheatham, T. E. (2013). PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. Journal of Chemical Theory and Computation, 9(7), 3084–3095. https://doi.org/10.1021/ct400341p
  • Ryckaert, J.-P., Ciccotti, G., & Berendsen, H. J. C. (1977). Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes. Journal of Computational Physics, 23(3), 327–341. https://doi.org/10.1016/0021-9991(77)90098-5
  • Sakamoto, K., Kamada, Y., Sameshima, T., Yaguchi, M., Niida, A., Sasaki, S., Miwa, M., Ohkubo, S., Sakamoto, J.-I., Kamaura, M., Cho, N., & Tani, A. (2017). K-Ras(G12D)-selective inhibitory peptides generated by random peptide T7 phage display technology. Biochemical and Biophysical Research Communications, 484(3), 605–611. https://doi.org/10.1016/j.bbrc.2017.01.147
  • Salentin, S., Schreiber, S., Haupt, V. J., Adasme, M. F., & Schroeder, M. (2015). PLIP: Fully automated protein–ligand interaction profiler. Nucleic Acids Research, 43(W1), W443–W447. https://doi.org/10.1093/nar/gkv315
  • Salomon-Ferrer, R., Case, D. A., & Walker, R. C. (2013a). An overview of the Amber biomolecular simulation package. Wiley Interdisciplinary Reviews: Computational Molecular Science, 3(2), 198–210. https://doi.org/10.1002/wcms.1121
  • Salomon-Ferrer, R., Götz, A. W., Poole, D., Le Grand, S., & Walker, R. C. (2013b). Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit solvent particle mesh Ewald. Journal of Chemical Theory and Computation, 9(9), 3878–3888. https://doi.org/10.1021/ct400314y
  • Sayyed-Ahmad, A., Prakash, P., & Gorfe, A. A. (2017). Distinct dynamics and interaction patterns in H- and K-Ras oncogenic P-loop mutants. Proteins, 85(9), 1618–1632. https://doi.org/10.1002/prot.25317
  • Shima, F., Ijiri, Y., Muraoka, S., Liao, J., Ye, M., Araki, M., Matsumoto, K., Yamamoto, N., Sugimoto, T., Yoshikawa, Y., Kumasaka, T., Yamamoto, M., Tamura, A., & Kataoka, T. (2010). Structural basis for conformational dynamics of GTP-bound Ras protein. The Journal of Biological Chemistry, 285(29), 22696–22705. https://doi.org/10.1074/jbc.M110.125161
  • Spiegel, J., Cromm, P. M., Zimmermann, G., Grossmann, T. N., & Waldmann, H. (2014). Small-molecule modulation of Ras signaling. Nature Chemical Biology, 10(8), 613–622. https://doi.org/10.1038/nchembio.1560
  • Spoerner, M., Herrmann, C., Vetter, I. R., Kalbitzer, H. R., & Wittinghofer, A. (2001). Dynamic properties of the Ras switch I region and its importance for binding to effectors. Proceedings of the National Academy of Sciences of the United States of America, 98(9), 4944–4949. https://doi.org/10.1073/pnas.081441398
  • Sun, H., Li, Y., Tian, S., Xu, L., & Hou, T. (2014). Assessing the performance of MM/PBSA and MM/GBSA methods. 4. Accuracies of MM/PBSA and MM/GBSA methodologies evaluated by various simulation protocols using PDBbind data set. Physical Chemistry Chemical Physics: PCCP, 16(31), 16719–16729. https://doi.org/10.1039/C4CP01388C
  • Sun, Z., Gong, Z., Xia, F., & He, X. (2021a). Ion dynamics and selectivity of Nav channels from molecular dynamics simulation. Chemical Physics. 548, 111245. https://doi.org/10.1016/j.chemphys.2021.111245
  • Sun, Z., Huai, Z., He, Q., & Liu, Z. (2021b). A general picture of Cucurbit[8]uril host–guest binding. Journal of Chemical Information and Modeling, 61(12), 6107–6134. https://doi.org/10.1021/acs.jcim.1c01208
  • Ting, P. Y., Johnson, C. W., Fang, C., Cao, X., Graeber, T. G., Mattos, C., & Colicelli, J. (2015). Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding. FASEB Journal: official Publication of the Federation of American Societies for Experimental Biology, 29(9), 3750–3761. https://doi.org/10.1096/fj.15-271510
  • Vetter, I. R., & Wittinghofer, A. (2001). The Guanine nucleotide-binding switch in three dimensions. Science (New York, N.Y.), 294(5545), 1299–1304. https://doi.org/10.1126/science.1062023
  • Wang, J., Arantes, P. R., Bhattarai, A., Hsu, R. V., Pawnikar, S., Huang, Y. ‐m M., Palermo, G., & Miao, Y. (2021a). Gaussian accelerated molecular dynamics: Principles and applications. WIREs Computational Molecular Science, 11(5), e1521. https://doi.org/10.1002/wcms.1521
  • Wang, J., Lan, L., Wu, X., Xu, L., & Miao, Y. (2022a). Mechanism of RNA recognition by a Musashi RNA-binding protein. Current Research in Structural Biology, 4, 10–20. https://doi.org/10.1016/j.crstbi.2021.12.002
  • Wang, J., & Miao, Y. (2019). Mechanistic insights into specific G protein interactions with adenosine receptors. The Journal of Physical Chemistry. B, 123(30), 6462–6473. https://doi.org/10.1021/acs.jpcb.9b04867
  • Wang, J., & Miao, Y. (2020). Peptide Gaussian accelerated molecular dynamics (Pep-GaMD): Enhanced sampling and free energy and kinetics calculations of peptide binding. The Journal of Chemical Physics, 153(15), 154109. https://doi.org/10.1063/5.0021399
  • Wang, J., Wang, W., Kollman, P. A., & Case, D. A. (2006). Automatic atom type and bond type perception in molecular mechanical calculations. Journal of Molecular Graphics & Modelling, 25(2), 247–260. https://doi.org/10.1016/j.jmgm.2005.12.005
  • Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A., & Case, D. A. (2004). Development and testing of a general amber force field. Journal of Computational Chemistry, 25(9), 1157–1174. https://doi.org/10.1002/jcc.20035
  • Wang, X. (2021). Conformational fluctuations in GTP-Bound K-Ras: A metadynamics perspective with harmonic linear discriminant analysis. Journal of Chemical Information and Modeling, 61(10), 5212–5222. https://doi.org/10.1021/acs.jcim.1c00844
  • Wang, Y., Ji, D., Lei, C., Chen, Y., Qiu, Y., Li, X., Li, M., Ni, D., Pu, J., Zhang, J., Fu, Q., Liu, Y., & Lu, S. (2021b). Mechanistic insights into the effect of phosphorylation on Ras conformational dynamics and its interactions with cell signaling proteins. Computational and Structural Biotechnology Journal, 19, 1184–1199. https://doi.org/10.1016/j.csbj.2021.01.044
  • Wang, Y., Li, M., Liang, W., Shi, X., Fan, J., Kong, R., Liu, Y., Zhang, J., Chen, T., & Lu, S. (2022b). Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor. Computational and Structural Biotechnology Journal, 20, 628–639. https://doi.org/10.1016/j.csbj.2022.01.015
  • Weiser, J., Shenkin, P. S., & Still, W. C. (1999). Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO). Journal of Computational Chemistry, 20(2), 217–230. https://doi.org/10.1002/(SICI)1096-987X(19990130)20:2<217::AID-JCC4>3.0.CO;2-A
  • Wu, S. L., Zhao, J., Sun, H. B., Li, H. Y., Yin, Y. Y., & Zhang, L. L. (2021). Insights into interaction mechanism of inhibitors E3T, E3H and E3B with CREB binding protein by using molecular dynamics simulations and MM-GBSA calculations. SAR and QSAR in Environmental Research, 32(3), 221–246. https://doi.org/10.1080/1062936X.2021.1887351
  • Xiong, D., Zhao, X., Luo, S., Cong, Y., Zhang, J. Z. H., & Duan, L. (2022a). Immune escape mechanisms of SARS-CoV-2 Delta and Omicron variants against two monoclonal antibodies that received emergency use authorization. The Journal of Physical Chemistry Letters, 13(26), 6064–6073. https://doi.org/10.1021/acs.jpclett.2c00912
  • Xiong, D., Zhao, X., Luo, S., Zhang, J. Z. H., & Duan, L. (2022b). Molecular Mechanism of the Non-Covalent Orally Targeted SARS-CoV-2 Mpro Inhibitor S-217622 and Computational Assessment of Its Effectiveness against Mainstream Variants. The Journal of Physical Chemistry Letters, 13(38), 8893–8901. https://doi.org/10.1021/acs.jpclett.2c02428
  • Xiong, Y., Zeng, J., Xia, F., Cui, Q., Deng, X., & Xu, X. (2022c). Conformations and binding pockets of HRas and its guanine nucleotide exchange factors complexes in the guanosine triphosphate exchange process. Journal of Computational Chemistry, 43(13), 906–916. https://doi.org/10.1002/jcc.26846
  • Xue, W., Wang, P., Tu, G., Yang, F., Zheng, G., Li, X., Li, X., Chen, Y., Yao, X., & Zhu, F. (2018a). Computational identification of the binding mechanism of a triple reuptake inhibitor amitifadine for the treatment of major depressive disorder. Physical Chemistry Chemical Physics: PCCP, 20(9), 6606–6616. https://doi.org/10.1039/C7CP07869B
  • Xue, W., Yang, F., Wang, P., Zheng, G., Chen, Y., Yao, X., & Zhu, F. (2018b). What contributes to serotonin–norepinephrine reuptake inhibitors’ dual-targeting mechanism? The key role of transmembrane domain 6 in human serotonin and norepinephrine transporters revealed by molecular dynamics simulation. ACS Chemical Neuroscience, 9(5), 1128–1140. https://doi.org/10.1021/acschemneuro.7b00490
  • Yan, F., Liu, X., Zhang, S., Su, J., Zhang, Q., & Chen, J. (2019). Electrostatic interaction-mediated conformational changes of adipocyte fatty acid binding protein probed by molecular dynamics simulation. Journal of Biomolecular Structure & Dynamics, 37(14), 3583–3595. https://doi.org/10.1080/07391102.2018.1520648
  • Yu, Y. X., Wang, W., Sun, H. B., Zhang, L. L., Wang, L. F., & Yin, Y. Y. (2022a). Decoding drug resistant mechanism of V32I, I50V and I84V mutations of HIV-1 protease on amprenavir binding by using molecular dynamics simulations and MM-GBSA calculations. SAR and QSAR in Environmental Research, 33(10), 805–831. https://doi.org/10.1080/1062936X.2022.2140708
  • Yu, Z., Su, H., Chen, J., & Hu, G. (2022b). Deciphering conformational changes of the GDP-bound NRAS induced by mutations G13D, Q61R, and C118S through Gaussian accelerated molecular dynamic simulations. Molecules, 27(17), 5596. https://doi.org/10.3390/molecules27175596
  • Zeng, J., Weng, J., Zhang, Y., Xia, F., Cui, Q., & Xu, X. (2021). Conformational features of Ras: Key hydrogen-bonding interactions of Gln61 in the intermediate state during GTP hydrolysis. The Journal of Physical Chemistry. B, 125(31), 8805–8813. https://doi.org/10.1021/acs.jpcb.1c04679
  • Zhang, H., Ni, D., Fan, J., Li, M., Zhang, J., Hua, C., Nussinov, R., & Lu, S. (2022). Markov state models and molecular dynamics simulations reveal the conformational transition of the intrinsically disordered hypervariable region of K-Ras4B to the ordered conformation. Journal of Chemical Information and Modeling, 62(17), 4222–4231. https://doi.org/10.1021/acs.jcim.2c00591
  • Zheng, Y., Ding, L., Meng, X., Potter, M., Kearney, A. L., Zhang, J., Sun, J., James, D. E., Yang, G., & Zhou, C. (2022). Structural insights into Ras regulation by SIN1. Proceedings of the National Academy of Sciences of the United States of America, 119(19), e2119990119. https://doi.org/10.1073/pnas.2119990119

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