Advanced search
Publication Cover
Journal of Enzyme Inhibition and Medicinal Chemistry Volume 38, 2023 - Issue 1
Submit an article Journal homepage
1,142
Views
8
CrossRef citations to date
0
Altmetric
Research Paper

Probing mutation-induced conformational transformation of the GTP/M-RAS complex through Gaussian accelerated molecular dynamics simulations

Huayin Baoa School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, ChinaCorrespondence[email protected]
View further author information
,
Wei Wangb School of Science, Shandong Jiaotong University, Jinan, ChinaView further author information
,
Haibo Sunb School of Science, Shandong Jiaotong University, Jinan, ChinaView further author information
&
Jianzhong Chenb School of Science, Shandong Jiaotong University, Jinan, ChinaCorrespondence[email protected] [email protected]
ORCID Iconhttps://orcid.org/0000-0003-1558-4398View further author information
ORCID Icon
Article: 2195995 | Received 16 Jan 2023, Accepted 22 Mar 2023, Published online: 14 Apr 2023

References

  • Barbacid M. ras GENES. Annu Rev Biochem. 1987;56:779–827.
  • Vojtek AB, Der CJ. Increasing complexity of the ras signaling pathway *. J Biol Chem. 1998;273(32):19925–19928.
  • Carratt SA, Braun TP, Coblentz C, Schonrock Z, Callahan R, Curtiss BM, Maloney L, Foley AC, Maxson JE. Correction: mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia. Leukemia. 2022;36(8):2149.
  • Chowers G, Abebe-Campino G, Golan H, et al. Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition. Pediatr. Res. 2022. DOI:10.1038/S41390-022-01986-0
  • Spiegel J, Cromm PM, Zimmermann G, Grossmann TN, Waldmann H. Small-molecule modulation of Ras signaling. Nat Chem Biol. 2014;10(8):613–622.
  • Ma J, Karplus M. Molecular switch in signal transduction: reaction paths of the conformational changes in ras p21. Proc Natl Acad Sci U S A. 1997;94(22):11905–11910.
  • Lu S, Jang H, Muratcioglu S, Gursoy A, Keskin O, Nussinov R, Zhang J. Ras conformational ensembles, allostery, and signaling. chem rev. 2016;116(11):6607–6665.
  • Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129(5):865–877.
  • Chen J, Zhang S, Wang W, Pang L, Zhang Q, Liu X. 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. J Chem Inf Model. 2021;61(4):1954–1969.
  • Pálfy G, Vida I, Perczel A. 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. Biomol NMR Assign. 2020;14(1):1–7.
  • Gorfe AA. Mechanisms of allostery and membrane attachment in Ras GTPases: implications for anti-cancer drug discovery. Curr Med Chem. 2010;17(1):1–9.
  • Yu Z, Su H, Chen J, et al. Deciphering conformational changes of the GDP-Bound NRAS induced by mutations G13D, Q61R, and C118S through Gaussian accelerated molecular dynamic simulations. Molecules. 2022;27:5596.
  • Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9(7):517–531.
  • Hernández-Porras I, Schuhmacher AJ, Garcia-Medina R, Jiménez B, Cañamero M, de Martino A, Guerra C. K-RasV14I-induced Noonan syndrome predisposes to tumour development in mice. J Pathol. 2016;239(2):206–217.
  • Jinesh GG, Sambandam V, Vijayaraghavan S, Balaji K, Mukherjee S. Molecular genetics and cellular events of K-Ras-driven tumorigenesis. Oncogene. 2018;37(7):839–846.
  • Ting PY, Johnson CW, Fang C, Cao X, Graeber TG, Mattos C, Colicelli J. Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding. Faseb J. 2015;29(9):3750–3761.
  • Ward KR, Zhang K-X, Somasiri AM, Roskelley CD, Schrader JW. Expression of activated M-Ras in a murine mammary epithelial cell line induces epithelial–mesenchymal transition and tumorigenesis. Oncogene. 2004;23(6):1187–1196.
  • Kessler D, Bergner A, Böttcher J, Fischer G, Döbel S, Hinkel M, Müllauer B, Weiss-Puxbaum A, McConnell DB. Drugging all RAS isoforms with one pocket. Future Med Chem. 2020;12(21):1911–1923.
  • Shima F, Ijiri Y, Muraoka S, Liao J, Ye M, Araki M, Matsumoto K, Yamamoto N, Sugimoto T, Yoshikawa Y, et al. Structural basis for conformational dynamics of GTP-bound Ras protein. J Biol Chem. 2010;285(29):22696–22705.
  • Parker JA, Volmar AY, Pavlopoulos S, Mattos C. K-Ras populates conformational states differently from its isoform H-Ras and oncogenic mutant K-RasG12D. Structure. 2018;26(6):810–820.e4.
  • Fraser JS, van den Bedem H, Samelson AJ, Lang PT, Holton JM, Echols N, Alber T. Accessing protein conformational ensembles using room-temperature X-ray crystallography. Proc Natl Acad Sci U S A. 2011;108(39):16247–16252.
  • Chen J, Zhang S, Zeng Q, et al. Free energy profiles relating with conformational transition of the switch domains induced by G12 mutations in GTP-bound KRAS. Front. Mol. Biosci. 2022;9:912518.
  • Corbett KD, Alber T. The many faces of Ras: recognition of small GTP-binding proteins. Trends Biochem Sci. 2001;26(12):710–716.
  • Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science. 2001;294(5545):1299–1304.
  • Nassar N, Horn G, Herrmann CA, et al. 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. 1995;375:554–560.
  • Pacold ME, Suire S, Perisic O, et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase. Cell. 2000;103:931–944.
  • Ye M, Shima F, Muraoka S, Liao J, Okamoto H, Yamamoto M, Tamura A, Yagi N, Ueki T, Kataoka T, et al. Crystal structure of M-Ras reveals a GTP-bound "Off" State conformation of Ras family small GTPases. J Biol Chem. 2005;280(35):31267–31275.
  • Spoerner M, Herrmann C, Vetter IR, Kalbitzer HR, Wittinghofer A. Dynamic properties of the Ras switch I region and its importance for binding to effectors. Proc Natl Acad Sci U S A. 2001;98(9):4944–4949.
  • Hocker HJ, Cho K-J, Chen C-YK, et al. Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function. Proc. Natl. Acad. Sci. USA. 2013;110:10201–10206.
  • Chen J, Wang L, Wang W, et al. 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. Comput. Biol. Med. 2021;135:104639.
  • Zeng J, Chen J, Xia F, et al. Identification of functional substates of KRas during GTP hydrolysis with enhanced sampling simulations. Phys. Chem. Chem. Phys. 2022;24:7653–7665.
  • Xiong Y, Zeng J, Xia F, et al. Conformations and binding pockets of HRas and its guanine nucleotide exchange factors complexes in the guanosine triphosphate exchange process. J. Comput. Chem. 2022;43:906–916.
  • Kimmelman A, Tolkacheva T, Lorenzi MV, et al. Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution. Oncogene. 1997;15:2675–2685.
  • Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C. M-Ras/R-Ras3, a transforming Ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. J Biol Chem. 1999;274(34):23850–23857.
  • Rodriguez-Viciana P, Sabatier C, McCormick F. Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol. Cell. Biol. 2004;24:4943–4954.
  • Ehrhardt GRA, Korherr C, Wieler JS, et al. A novel potential effector of M-Ras and p21 Ras negatively regulates p21 Ras-mediated gene induction and cell growth. Oncogene. 2001;20:188–197.
  • Matsumoto K, Asano T, Endo T. Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton. Oncogene. 1997;15:2409–2417.
  • Guo X, Schrader KA, Xu Y, et al. Expression of a constitutively active mutant of M-Ras in normal bone marrow is sufficient for induction of a malignant mastocytosis/mast cell leukemia, distinct from the histiocytosis/monocytic leukemia induced by expression of activated H-Ras. Oncogene. 2005;24:2330–2342.
  • Guo X, Stratton L, Schrader JW. Expression of activated M-Ras in hemopoietic stem cells initiates leukemogenic transformation, immortalization and preferential generation of mast cells. Oncogene. 2006;25:4241–4244.
  • Wang L, Lu D, Wang Y, et al. Binding selectivity-dependent molecular mechanism of inhibitors towards CDK2 and CDK6 investigated by multiple short molecular dynamics and free energy landscapes. J. Enzym. Inhib. Med. Chem. 2023;38:84–99.
  • Wang J, Lan L, Wu X, et al. Mechanism of RNA recognition by a Musashi RNA-binding protein. Curr. Res. Struct. Biol. 2022;4:10–20.
  • Hou T, Yu R. 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. J Med Chem. 2007;50(6):1177–1188.
  • Xue W, Wang P, Tu G, et al. Computational identification of the binding mechanism of a triple reuptake inhibitor amitifadine for the treatment of major depressive disorder. Phys. Chem. Chem. Phys. 2018;20:6606–6616.
  • Sun H, Li Y, Shen M, et al. Assessing the performance of MM/PBSA and MM/GBSA methods. 5. Improved docking performance using high solute dielectric constant MM/GBSA and MM/PBSA rescoring. Phys. Chem. Chem. Phys. 2014;16:22035–22045.
  • Sun Z, Gong Z, Xia F, et al. Ion dynamics and selectivity of Nav channels from molecular dynamics simulation. Chem. Phys. 2021;548:111245.
  • Antunes D, Santos LHS, Caffarena ER, et al. Bacterial 2′-deoxyguanosine riboswitch classes as potential targets for antibiotics: a structure and dynamics study. Int. J. Mol. Sci. 2022;23:1925.
  • Chen J. Drug resistance mechanisms of three mutations V32I, I47V and V82I in HIV-1 protease toward inhibitors probed by molecular dynamics simulations and binding free energy predictions. RSC Adv. 2016;6:58573–58585.
  • Poli G, Barravecchia I, Demontis GC, et al. Predicting potentially pathogenic effects of hRPE65 missense mutations: a computational strategy based on molecular dynamics simulations. J. Enzym. Inhib. Med. Chem. 2022;37:1765–1772.
  • Li M, Liu X, Zhang S, et al. Deciphering the binding mechanism of inhibitors of the SARS-CoV-2 main protease through multiple replica accelerated molecular dynamics simulations and free energy landscapes. Phys. Chem. Chem. Phys. 2022;24:22129–22143.
  • Sun H, Li Y, Tian S, et al. 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. Phys. Chem. Chem. Phys. 2014;16:16719–16729.
  • Chen J, Zeng Q, Wang W, et al. Decoding the identification mechanism of an SAM-III Riboswitch on ligands through multiple independent Gaussian-accelerated molecular dynamics simulations. J. Chem. Inf. Model. 2022;62:6118–6132.
  • Sun Z, Huai Z, He Q, et al. A general picture of cucurbit[8]uril host–guest binding. J. Chem. Inf. Model. 2021;61:6107–6134.
  • Chen J, Wang J, Zeng Q, et al. Exploring the deactivation mechanism of human β2 adrenergic receptor by accelerated molecular dynamic simulations. Front. Mol. Biosci. 2022;9:972463.
  • Xue W, Yang F, Wang P, et al. 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 Chem. Neurosci. 2018;9:1128–1140.
  • Pierce LCT, Salomon-Ferrer R, Augusto F, de Oliveira C, et al. Routine access to millisecond time scale events with accelerated molecular dynamics. J. Chem. Theory Comput. 2012;8:2997–3002.
  • Miao Y, Feher VA, McCammon JA. Gaussian accelerated molecular dynamics: unconstrained enhanced sampling and free energy calculation. J. Chem. Theory Comput. 2015;11:3584–3595.
  • Wang J, Arantes PR, Bhattarai A, et al. Gaussian accelerated molecular dynamics: principles and applications. WIREs Comput. Mol. Sci. 2021;11:e1521.
  • Wang J, Miao Y. Peptide Gaussian accelerated molecular dynamics (Pep-GaMD): Enhanced sampling and free energy and kinetics calculations of peptide binding. J. Chem. Phys. 2020;153:154109.
  • Wang J, Miao Y. Mechanistic insights into specific G protein interactions with adenosine receptors. J. Phys. Chem. B. 2019;123:6462–6473.
  • Miao Y, McCammon JA. Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor. Proc. Natl. Acad. Sci. USA. 2018;115:3036–3041.
  • Chen J, Zhang S, Wang W, et al. Binding of inhibitors to BACE1 affected by pH-dependent protonation: an exploration from multiple replica gaussian accelerated molecular dynamics and MM-GBSA calculations. ACS Chem. Neurosci. 2021;12:2591–2607.
  • Wang Y, Li M, Liang W, et al. Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor. Comput. Struct. Biotec. 2022;20:628–639.
  • Amadei A, Linssen ABM, Berendsen HJC. Essential dynamics of proteins. Proteins. 1993;17:412–425.
  • Laberge M, Yonetani T. Molecular dynamics simulations of hemoglobin A in different states and bound to DPG: effector-linked perturbation of tertiary conformations and HbA concerted dynamics. Biophys J. 2008;94(7):2737–2751.
  • Chen J, Wang W, Sun H, et al. Binding mechanism of inhibitors to p38α MAP kinase deciphered by using multiple replica Gaussian accelerated molecular dynamics and calculations of binding free energies. Comput. Biol. Med. 2021;134:104485.
  • Levy RM, Srinivasan AR, Olson WK, McCammon JA. Quasi-harmonic method for studying very low frequency modes in proteins. Biopolymers. 1984;23(6):1099–1112.
  • Bao HY, Wang W, Sun HB, et al. Binding modes of GDP, GTP and GNP to NRAS deciphered by using Gaussian accelerated molecular dynamics simulations. SAR QSAR Environ. Res. 2023;34:65–89.
  • Xu S, Long BN, Boris GH, et al. Structural insight into the rearrangement of the switch I region in GTP-bound G12A K-Ras. Acta Cryst. 2017;73:970–984.
  • Anandakrishnan R, Aguilar B, Onufriev AV. H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations. Nucleic Acids Res. 2012;40:W537–W41.
  • Salomon-Ferrer R, Case DA, Walker RC. An overview of the Amber biomolecular simulation package. WIREs Comput. Mol. Sci. 2013;3:198–210.
  • Case DA, Cheatham TE, III Darden T, et al. The Amber biomolecular simulation programs. J. Comput. Chem. 2005;26:1668–1688.
  • Tian C, Kasavajhala K, Belfon KAA, et al. ff19SB: amino-acid-specific protein backbone parameters trained against quantum mechanics energy surfaces in solution. J. Chem. Theory Comput. 2020;16:528–552.
  • Meagher KL, Redman LT, Carlson HA. Development of polyphosphate parameters for use with the AMBER force field. J. Comput. Chem. 2003;24:1016–1025.
  • Jorgensen WL, Chandrasekhar J, Madura JD, et al. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983;79:926–935.
  • Joung IS, Cheatham TE. III. Determination of alkali and halide monovalent ion parameters for use in explicitly solvated biomolecular simulations. J. Phys. Chem. B. 2008;112:9020–9041.
  • Joung IS, Cheatham TE. III. Molecular dynamics simulations of the dynamic and energetic properties of alkali and halide ions using water-model-specific ion parameters. J. Phys. Chem. 2009;113:13279–13290. B
  • Essmann U, Perera L, Berkowitz ML, et al. A smooth particle mesh Ewald method. J. Chem. Phys. 1995;103:8577–8593.
  • Miao Y, Sinko W, Pierce L, et al. Improved reweighting of accelerated molecular dynamics simulations for free energy calculation. J. Chem. Theory Comput. 2014;10:2677–2689.
  • Ryckaert J-P, Ciccotti G, Berendsen HJC. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys. 1977;23:327–341.
  • Izaguirre JA, Catarello DP, Wozniak JM, et al. Langevin stabilization of molecular dynamics. J. Chem. Phys. 2001;114:2090–2098.
  • Salomon-Ferrer R, Götz AW, Poole D, et al. Routine microsecond molecular dynamics simulations with amber on gpus. 2. explicit solvent particle mesh Ewald. J. Chem. Theory Comput. 2013;9:3878–3888.
  • Götz AW, Williamson MJ, Xu D, et al. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 1. generalized born. J. Chem. Theory Comput. 2012;8:1542–1555.
  • Chen J, Zeng Q, Wang W, et al. Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes. RSC Adv. 2022;12:1742–1757.
  • Ichiye T, Karplus M. Collective motions in proteins: a covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations. Proteins. 1991;11(3):205–217.
  • Liang SS, Liu XG, Cui YX, et al. Molecular mechanism concerning conformational changes of CDK2 mediated by binding of inhibitors using molecular dynamics simulations and principal component analysis. SAR QSAR Environ. Res. 2021;32:573–594.
  • Yan F, Liu X, Zhang S, et al. Molecular dynamics exploration of selectivity of dual inhibitors 5M7, 65X, and 65Z toward Fatty acid binding proteins 4 and 5. Int. J. Mol. Sci. 2018;19:2496.
  • Roe DR, Cheatham TE. III. PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput. 2013;9:3084–3095.
  • Tsai C-J, Ma B, Nussinov R. Folding and binding cascades: shifts in energy landscapes. Proc. Natl. Acad. Sci. USA. 1999;96:9970–9972.
  • Chen J, Wang J, Zhu W. Molecular mechanism and energy basis of conformational diversity of antibody spe7 revealed by molecular dynamics simulation and principal component analysis. Sci. Rep. 2016;6:36900.
  • Weiser J, Shenkin PS, Still WC. Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO). J. Comput. Chem. 1999;20:217–230.
  • Franken SM, Scheidig AJ, Krengel U, et al. Three-dimensional structures and properties of a transforming and a nontransforming glycine-12 mutant of p21H-ras. Biochemistry. 1993;32:8411–8420.
  • Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J. The structural basis of the activation of Ras by Sos. Nature. 1998;394(6691):337–343.
  • Ito Y, Yamasaki K, Iwahara J, et al. Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein. Biochemistry. 1997;36:9109–9119.
  • Ahmadian MR, Zor T, Vogt D, et al. Guanosine triphosphatase stimulation of oncogenic Ras mutants. Proc. Natl. Acad. Sci. USA. 1999;96:7065. 70.
  • Cherfils J, Ménétrey J, Le Bras G, Janoueix-Lerosey I, de Gunzburg J, Garel JR, Auzat I. Crystal structures of the small G protein Rap2A in complex with its substrate GTP, with GDP and with GTPγS. Embo J. 1997;16(18):5582–5591.
  • Henzler-Wildman K, Kern D. Dynamic personalities of proteins. Nature. 2007;450(7172):964–972.
  • Adasme MF, Linnemann KL, Bolz SN, et al. PLIP 2021: expanding the scope of the protein–ligand interaction profiler to DNA and RNA. Nucleic Acids Res. 2021;49:W530. W4.
  • Salentin S, Schreiber S, Haupt VJ, et al. PLIP: fully automated protein–ligand interaction profiler. Nucleic Acids Res. 2015;43:W443–W7.
  • Buhrman G, Kumar VSS, Cirit M, Haugh JM, Mattos C. Allosteric modulation of Ras-GTP Is linked to signal transduction through RAF kinase. J Biol Chem. 2011;286(5):3323–3331.
  • Khaled M, Gorfe A, Sayyed-Ahmad A. Conformational and dynamical Effects of Tyr32 phosphorylation in K-Ras: molecular dynamics simulation and Markov state models analysis. J. Phys. Chem. B. 2019;123:7667–7675.
  • Johnson CW, Reid D, Parker JA, Salter S, Knihtila R, Kuzmic P, Mattos C. The small GTPases K-Ras, N-Ras, and H-Ras have distinct biochemical properties determined by allosteric effects. J Biol Chem. 2017;292(31):12981–12993.
  • Gorfe AA, Grant BJ, McCammon JA. Mapping the nucleotide and isoform-dependent structural and dynamical features of Ras proteins. Structure. 2008;16:885–896.
  • Chen S, Shu L, Zhao R, Zhao Y. Molecular dynamics simulations reveal the activation mechanism of mutations G12V and Q61L of Cdc42. Proteins. 2022;90(7):1376–1389.
  • Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J. Mol. Graph. 1996;14:33–38.
  • Hu Z, Marti J. 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. Int. J. Mol. Sci. 2022;23:13865.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.