Skip to main content

New insights from molecular dynamic simulation studies of the multiple binding modes of a ligand with G-quadruplex DNA

Journal of Computer-Aided Molecular Design volume 26, pages 1355–1368 (2012)Cite this article

Abstract

G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences. These structures have recently emerged as a new class of potential molecular targets for anticancer drugs. An understanding of the three-dimensional interactions between small molecular ligands and their G-quadruplex targets in solution is crucial for rational drug design and the effective optimization of G-quadruplex ligands. Thus far, rational ligand design has been focused mainly on the G-quartet platform. It should be noted that small molecules can also bind to loop nucleotides, as observed in crystallography studies. Hence, it would be interesting to elucidate the mechanism underlying how ligands in distinct binding modes influence the flexibility of G-quadruplex. In the present study, based on a crystal structure analysis, the models of a tetra-substituted naphthalene diimide ligand bound to a telomeric G-quadruplex with different modes were built and simulated with a molecular dynamics simulation method. Based on a series of computational analyses, the structures, dynamics, and interactions of ligand-quadruplex complexes were studied. Our results suggest that the binding of the ligand to the loop is viable in aqueous solutions but dependent on the particular arrangement of the loop. The binding of the ligand to the loop enhances the flexibility of the G-quadruplex, while the binding of the ligand simultaneously to both the quartet and the loop diminishes its flexibility. These results add to our understanding of the effect of a ligand with different binding modes on G-quadruplex flexibility. Such an understanding will aid in the rational design of more selective and effective G-quadruplex binding ligands.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Burge S, Parkinson GN, Hazel P, Todd AK, Neidle S (2006) Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res 34:5402–5415

    Article  CAS  Google Scholar 

  2. Dai J, Carver M, Yang D (2008) Polymorphism of human telomeric quadruplex structures. Biochimie 90:1172–1183

    Article  CAS  Google Scholar 

  3. Davis JT (2004) G-quartets 40 years later: from 5′-GMP to molecular biology and supramolecular chemistry. Angew Chem Int Ed Engl 43:668–698

    Article  CAS  Google Scholar 

  4. Henderson E, Hardin CC, Walk SK, Tinoco I Jr, Blackburn EH (1987) Telomeric DNA oligonucleotides form novel intramolecular structures containing guanine–guanine base pairs. Cell 51:899–908

    Article  CAS  Google Scholar 

  5. Dexheimer TS, Sun D, Hurley LH (2006) Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. J Am Chem Soc 128:5404–5415

    Article  CAS  Google Scholar 

  6. Rankin S, Reszka AP, Huppert J, Zloh M, Parkinson GN et al (2005) Putative DNA quadruplex formation within the human c-kit oncogene. J Am Chem Soc 127:10584–10589

    Article  CAS  Google Scholar 

  7. Simonsson T, Pecinka P, Kubista M (1998) DNA tetraplex formation in the control region of c-myc. Nucleic Acids Res 26:1167–1172

    Article  CAS  Google Scholar 

  8. Sen D, Gilbert W (1988) Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature 334:364–366

    Article  CAS  Google Scholar 

  9. Hanakahi LA, Sun H, Maizels N (1999) High affinity interactions of nucleolin with G–G-paired rDNA. J Biol Chem 274:15908–15912

    Article  CAS  Google Scholar 

  10. Harrison RJ, Cuesta J, Chessari G, Read MA, Basra SK et al (2003) Trisubstituted acridine derivatives as potent and selective telomerase inhibitors. J Med Chem 46:4463–4476

    Article  CAS  Google Scholar 

  11. Tan JH, Ou TM, Hou JQ, Lu YJ, Huang SL et al (2009) Isaindigotone derivatives: a new class of highly selective ligands for telomeric G-quadruplex DNA. J Med Chem 52:2825–2835

    Article  CAS  Google Scholar 

  12. Oganesian L, Bryan TM (2007) Physiological relevance of telomeric G-quadruplex formation: a potential drug target. BioEssays 29:155–165

    Article  CAS  Google Scholar 

  13. Paeschke K, Simonsson T, Postberg J, Rhodes D, Lipps HJ (2005) Telomere end-binding proteins control the formation of G-quadruplex DNA structures in vivo. Nat Struct Mol Biol 12:847–854

    Article  CAS  Google Scholar 

  14. Duquette ML, Handa P, Vincent JA, Taylor AF, Maizels N (2004) Intracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA. Genes Dev 18:1618–1629

    Article  CAS  Google Scholar 

  15. Baumann P, Cech TR (2001) Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292:1171–1175

    Article  CAS  Google Scholar 

  16. Dexheimer TS, Carey SS, Zuohe S, Gokhale VM, Hu X et al (2009) NM23-H2 may play an indirect role in transcriptional activation of c-myc gene expression but does not cleave the nuclease hypersensitive element III1. Mol Cancer Ther 8:1363–1377

    Article  CAS  Google Scholar 

  17. Haider SM, Parkinson GN, Neidle S (2003) Structure of a G-quadruplex-ligand complex. J Mol Biol 326:117–125

    Article  CAS  Google Scholar 

  18. Campbell NH, Parkinson GN, Reszka AP, Neidle S (2008) Structural basis of DNA quadruplex recognition by an acridine drug. J Am Chem Soc 130:6722–6724

    Article  CAS  Google Scholar 

  19. Clark GR, Pytel PD, Squire CJ, Neidle S (2003) Structure of the first parallel DNA quadruplex-drug complex. J Am Chem Soc 125:4066–4067

    Article  CAS  Google Scholar 

  20. Gavathiotis E, Heald RA, Stevens MF, Searle MS (2003) Drug recognition and stabilisation of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat. J Mol Biol 334:25–36

    Article  CAS  Google Scholar 

  21. Hounsou C, Guittat L, Monchaud D, Jourdan M, Saettel N et al (2007) G-Quadruplex Recognition by Quinacridines: a SAR, NMR, and Biological Study. ChemMedChem 2:655–666

    Article  CAS  Google Scholar 

  22. Phan AT, Kuryavyi V, Gaw HY, Patel DJ (2005) Small-molecule interaction with a five-guanine-tract G-quadruplex structure from the human MYC promoter. Nat Chem Biol 1:167–173

    Article  CAS  Google Scholar 

  23. Neidle S (2009) The structures of quadruplex nucleic acids and their drug complexes. Curr Opin Struct Biol 19:239–250

    Article  CAS  Google Scholar 

  24. Neidle S, Parkinson GN (2008) Quadruplex DNA crystal structures and drug design. Biochimie 90:1184–1196

    Article  CAS  Google Scholar 

  25. Parkinson GN, Ghosh R, Neidle S (2007) Structural basis for binding of porphyrin to human telomeres. Biochemistry 46:2390–2397

    Article  CAS  Google Scholar 

  26. Parkinson GN, Cuenca F, Neidle S (2008) Topology conservation and loop flexibility in quadruplex-drug recognition: crystal structures of inter- and intramolecular telomeric DNA quadruplex-drug complexes. J Mol Biol 381:1145–1156

    Article  CAS  Google Scholar 

  27. Yang D, Okamoto K (2010) Structural insights into G-quadruplexes: towards new anticancer drugs. Future Med Chem 2:619–646

    Article  CAS  Google Scholar 

  28. Padmanabhan K, Padmanabhan KP, Ferrara JD, Sadler JE, Tulinsky A (1993) The structure of alpha-thrombin inhibited by a 15-mer single-stranded DNA aptamer. J Biol Chem 268:17651–17654

    CAS  Google Scholar 

  29. Schonhoft JD, Das A, Achamyeleh F, Samdani S, Sewell A et al (2009) ILPR repeats adopt diverse G-quadruplex conformations that determine insulin binding. Biopolymers 93:21–31

    Article  Google Scholar 

  30. Rodriguez D, Pineiro A, Gutierrez-de-Teran H (2011) Molecular dynamics simulations reveal insights into key structural elements of adenosine receptors. Biochemistry 50:4194–4208

    Article  CAS  Google Scholar 

  31. Moore MJ, Schultes CM, Cuesta J, Cuenca F, Gunaratnam M et al (2006) Trisubstituted acridines as G-quadruplex telomere targeting agents. Effects of extensions of the 3,6- and 9-side chains on quadruplex binding, telomerase activity, and cell proliferation. J Med Chem 49:582–599

    Article  CAS  Google Scholar 

  32. Cheatham TE 3rd (2004) Simulation and modeling of nucleic acid structure, dynamics and interactions. Curr Opin Struct Biol 14:360–367

    Article  CAS  Google Scholar 

  33. Chowdhury S, Bansal M (2001) G-quadruplex structure can be stable with only some coordination sites being occupied by cations: a six-nanosecond molecular dynamics study. J Phys Chem B 105:7572–7578

    Article  CAS  Google Scholar 

  34. Spackova N, Berger I, Sponer J (2001) Structural dynamics and cation interactions of DNA quadruplex molecules containing mixed guanine/cytosine quartets revealed by large-scale MD simulations. J Am Chem Soc 123:3295–3307

    Article  CAS  Google Scholar 

  35. Fadrna E, Spackova N, Stefl R, Koca J, Cheatham TE 3rd et al (2004) Molecular dynamics simulations of guanine quadruplex loops: advances and force field limitations. Biophys J 87:227–242

    Article  CAS  Google Scholar 

  36. Sponer J, Spackova N (2007) Molecular dynamics simulations and their application to four-stranded DNA. Methods 43:278–290

    Article  CAS  Google Scholar 

  37. Haider S, Parkinson GN, Neidle S (2008) Molecular dynamics and principal components analysis of human telomeric quadruplex multimers. Biophys J 95:296–311

    Article  CAS  Google Scholar 

  38. Yang DY, Chang TC, Sheu SY (2007) Interaction between human telomere and a carbazole derivative: a molecular dynamics simulation of a quadruplex stabilizer and telomerase inhibitor. J Phys Chem A 111:9224–9232

    Article  CAS  Google Scholar 

  39. Agrawal S, Ojha RP, Maiti S (2008) Energetics of the human Tel-22 quadruplex-telomestatin interaction: a molecular dynamics study. J Phys Chem B 112:6828–6836

    Article  CAS  Google Scholar 

  40. Cavallari M, Garbesi A, Di Felice R (2009) Porphyrin intercalation in G4-DNA quadruplexes by molecular dynamics simulations. J Phys Chem B 113:13152–13160

    Article  CAS  Google Scholar 

  41. Frisch, MJT, Trucks GW, Schlegel HB, Scuseria GE, Robb MA et al. (2004) Gaussian 03, Revision E.01; Gaussian, Inc, Wallingford, CT

  42. Case DA, Cheatham TE 3rd, Darden T, Gohlke H, Luo R et al (2005) The Amber biomolecular simulation programs. J Comput Chem 26:1668–1688

    Article  CAS  Google Scholar 

  43. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25:1157–1174

    Article  CAS  Google Scholar 

  44. Cornell WD, Cieplak P, Bayly CI, Gould IR Jr, Ferguson DM et al (1995) A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J Am Chem Soc 117:5179

    Article  CAS  Google Scholar 

  45. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341

    Article  CAS  Google Scholar 

  46. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  47. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(33–38):27–28

    Google Scholar 

  48. Kollman PA, Massova I, Reyes C, Kuhn B, Huo S et al (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–897

    Article  CAS  Google Scholar 

  49. Fogolari F, Brigo A, Molinari H (2003) Protocol for MM/PBSA molecular dynamics simulations of proteins. Biophys J 85:159–166

    Article  CAS  Google Scholar 

  50. Hazel P, Parkinson GN, Neidle S (2006) Predictive modelling of topology and loop variations in dimeric DNA quadruplex structures. Nucleic Acids Res 34:2117–2127

    Article  CAS  Google Scholar 

  51. Zeng J, Li W, Zhao Y, Liu G, Tang Y et al (2008) Insights into ligand selectivity in estrogen receptor isoforms: molecular dynamics simulations and binding free energy calculations. J Phys Chem B 112:2719–2726

    Article  CAS  Google Scholar 

  52. Gilson MK, Sharp KA, Honig B (1987) Calculating electrostatic interactions in biomolecules: method and error assessment. J Comput Chem 9:327–335

    Article  Google Scholar 

  53. Still WC, Tempczyk A, Hawley RC, Hendrickson T (1990) Semianalytical treatment of solvation for molecular mechanics and dynamics. J Am Chem Soc 112:6127–6129

    Article  CAS  Google Scholar 

  54. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM et al (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612

    Article  CAS  Google Scholar 

  55. Amadei A, Linssen AB, Berendsen HJ (1993) Essential dynamics of proteins. Proteins 17:412–425

    Article  CAS  Google Scholar 

  56. Amadei A, Linssen AB, de Groot BL, van Aalten DM, Berendsen HJ (1996) An efficient method for sampling the essential subspace of proteins. J Biomol Struct Dyn 13:615–625

    Article  CAS  Google Scholar 

  57. Meyer T, Ferrer-Costa C, Perez A, Rueda M, Bidon-Chanal A et al (2006) Essential dynamics: a tool for efficient trajectory compression and management. J Chem Theory Comput 2:251–258

    Article  CAS  Google Scholar 

  58. DeLano WL (2002) The PyMOL molecular graphics system. DeLano Scientific, San Carlos, CA

    Google Scholar 

  59. Podbevsek P, Hud NV, Plavec J (2007) NMR evaluation of ammonium ion movement within a unimolecular G-quadruplex in solution. Nucleic Acids Res 35:2554–2563

    Article  CAS  Google Scholar 

  60. Podbevsek P, Sket P, Plavec J (2008) Stacking and not solely topology of T3 loops controls rigidity and ammonium ion movement within d(G4T3G4)2 G-quadruplex. J Am Chem Soc 130:14287–14293

    Article  CAS  Google Scholar 

  61. Sket P, Plavec J (2010) Tetramolecular DNA Quadruplexes in solution: insights into structural diversity and cation movement. J Am Chem Soc 132:12724–12732

    Article  CAS  Google Scholar 

  62. Hou JQ, Chen SB, Tan JH, Ou TM, Luo HB et al (2010) New insights into the structures of ligand-quadruplex complexes from molecular dynamics simulations. J Phys Chem B 114:15301–15310

    Article  CAS  Google Scholar 

  63. Zavasnik J, Podbevsek P, Plavec J (2011) Observation of water molecules within the bimolecular d(G3CT4G3C)2 G-quadruplex. Biochemistry 50:4155–4161

    Article  CAS  Google Scholar 

  64. Miller MC, Buscaglia R, Chaires JB, Lane AN, Trent JO (2010) Hydration is a major determinant of the G-quadruplex stability and conformation of the human telomere 3′ sequence of d(AG3(TTAG3)3). J Am Chem Soc 132:17105–17107

    Article  CAS  Google Scholar 

  65. Fan HY, Shek YL, Amiri A, Dubins DN, Heerklotz H et al (2011) Volumetric characterization of sodium-induced G-quadruplex formation. J Am Chem Soc 133:4518–4526

    Article  CAS  Google Scholar 

  66. Stefl R, Spackova N, Berger I, Koca J, Sponer J (2001) Molecular dynamics of DNA quadruplex molecules containing inosine, 6-thioguanine and 6-thiopurine. Biophys J 80:455–468

    Article  CAS  Google Scholar 

  67. Stefl R, Cheatham TE 3rd, Spackova N, Fadrna E, Berger I et al (2003) Formation pathways of a guanine-quadruplex DNA revealed by molecular dynamics and thermodynamic analysis of the substates. Biophys J 85:1787–1804

    Article  CAS  Google Scholar 

  68. Cang X, Sponer J, Cheatham TE 3rd (2011) Explaining the varied glycosidic conformational, G-tract length and sequence preferences for anti-parallel G-quadruplexes. Nucleic Acids Res 39:4499–4512

    Article  CAS  Google Scholar 

  69. Yue DJ, Lim KW, Phan AT (2011) Formation of (3 + 1) G-quadruplexes with a long loop by human telomeric DNA spanning five or more repeats. J Am Chem Soc 133:11462–11465

    Article  CAS  Google Scholar 

  70. Collie GW, Promontorio R, Hampel SM, Micco M, Neidle S, Parkinson GN (2012) Structural basis for telomeric G-quadruplex targeting by naphthalene diimide ligands. J Am Chem Soc 134:2723

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank the Natural Science Foundation of China (Grants U0832005, 90813011, 21172272), the International S&T Cooperation Program of China (2010DFA34630), and the Science Foundation of Guangzhou (2009A1-E011-6) for their financial support of this study. The water oxygen density contours were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR001081).

Author information

Affiliations

  1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

    Jin-Qiang Hou, Shuo-Bin Chen, Jia-Heng Tan, Hai-Bin Luo, Ding Li, Lian-Quan Gu & Zhi-Shu Huang

Authors
  1. Jin-Qiang Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuo-Bin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jia-Heng Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hai-Bin Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ding Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lian-Quan Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhi-Shu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lian-Quan Gu or Zhi-Shu Huang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10822_2012_9619_MOESM1_ESM.doc

Figures showing ligand charges calculated with HF/6-31G* basis set and followed by RESP calculation (Figure S1); Time dependence of the RMSD of G-quartet heavy atoms (black) and backbone of G-quadruplex (red) (Figure S2); The planes of the first, second and fourth principal components for all the simulations (Figure S3) (DOC 3456 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hou, JQ., Chen, SB., Tan, JH. et al. New insights from molecular dynamic simulation studies of the multiple binding modes of a ligand with G-quadruplex DNA. J Comput Aided Mol Des 26, 1355–1368 (2012). https://doi.org/10.1007/s10822-012-9619-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-012-9619-1

Keywords

  • Molecular dynamics simulation
  • Telomeric G-quadruplex DNA
  • Naphthalene diimide derivative
  • Binding modes