A computational analysis of d(GGGGTTTTGGGG)(2) guanine quadruplexes containing either lateral or diagonal four-thymidine loops was carried out using molecular dynamics (MD) simulations in explicit solvent, locally enhanced sampling (LES) simulations, systematic conformational search, and free energy molecular-mechanics, Poisson Boltzmann, surface area (MM-PBSA) calculations with explicit inclusion of structural monovalent cations. The study provides, within the approximations of the applied all-atom additive force field, a qualitatively complete analysis of the available loop conformational space. The results are independent of the starting structures. Major conformational transitions not seen in conventional MD simulations are observed when LES is applied. The favored LES structures consistently provide lower free energies (as estimated by molecular-mechanics, Poisson Boltzmann, surface area) than other structures. Unfortunately, the predicted optimal structure for the diagonal loop arrangement differs substantially from the atomic resolution experiments. This result is attributed to force field deficiencies, such as the potential misbalance between solute-cation and solvent-cation terms. The MD simulations are unable to maintain the stable coordination of the monovalent cations inside the diagonal loops as reported in a recent x-ray study. The optimal diagonal and lateral loop arrangements appear to be close in energy although a proper inclusion of the loop monovalent cations could stabilize the diagonal architecture.

National Centre for Biomolecular Research Faculty of Science Masaryk University 611 37 Brno Czech Republic

Zobrazit více v PubMed

Balagurumoorthy, P., and S. K. Brahmachari. 1994. Structure and stability of human telomeric sequence. J. Biol. Chem. 269:21858–21869. PubMed

Balagurumoorthy, P., S. K. Brahmachari, D. Mohanty, M. Bansal, and V. Sasisekharan. 1992. Hairpin and parallel quartet structures for telomeric sequences. Nucleic Acids Res. 20:4061–4067. PubMed PMC

Berendsen, H. J. C., J. P. M. Postma, W. F. Vangunsteren, A. Dinola, and J. R. Haak. 1984. Molecular-dynamics with coupling to an external bath. J. Chem. Phys. 81:3684–3690.

Beveridge, D. L., and K. J. McConnell. 2000. Nucleic acids: theory and computer simulation, Y2K. Curr. Opin. Struct. Biol. 10:182–196. PubMed

Bouaziz, S., A. Kettani, and D. J. Patel. 1998. A K cation-induced conformational switch within a loop spanning segment of a DNA quadruplex containing G-G-G-C repeats. J. Mol. Biol. 282:637–652. PubMed

Case, D. A., D. A. Pearlman, J. W. Caldwell, T. E. Cheatham, W. S. Ross, T. A. Simmerling, T. A. Darden, K. M. Merz, R. V. Stanton, A. L. Cheng, J. J. Vincent, M. Crowley, D. M. Ferguson, R. J. Radmer, G. L. Seibel, U. C. Singh, P. K. Weiner, and P. A. Kollman. 1997. AMBER Version 5. University of California, San Francisco.

Cheatham, T. E., 3rd. 2004. Simulation and modeling of nucleic acid structure, dynamics and interactions. Cur. Op. Struct. Biol. 14:360–367. PubMed

Cheatham, T. E., 3rd, P. Cieplak, and P. A. Kollman. 1999. A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat. J. Biomol. Struct. Dyn. 16:845–862. PubMed

Cheatham, T. E., 3rd, J. L. Miller, T. Fox, T. A. Darden, and P. A. Kollman. 1995. Molecular-dynamics simulations on solvated biomolecular systems: the particle mesh Ewald method leads to stable trajectories of DNA, RNA, and proteins. J. Am. Chem. Soc. 117:4193–4194.

Cheatham, T. E., 3rd, and M. A. Young. 2000. Molecular dynamics simulation of nucleic acids: successes, limitations, and promise. Biopolymers. 56:232–256. PubMed

Chowdhury, S., and M. Bansal. 2001a. 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.

Chowdhury, S., and M. Bansal. 2001b. A nanosecond molecular dynamics study of antiparallel d(G)(7) quadruplex structures: effect of the coordinated cations. J. Biomol. Struct. Dyn. 18:647–669. PubMed

Cornell, W. D., P. Cieplak, C. I. Bayly, I. R. Gould, K. M. Merz, D. M. Ferguson, D. C. Spellmeyer, T. Fox, J. W. Caldwell, and P. A. Kollman. 1995. A 2nd generation force-field for the simulation of proteins, nucleic-acids, and organic-molecules. J. Am. Chem. Soc. 117:5179–5197.

Crnugelj, M., N. V. Hud, and J. Plavec. 2002. The solution structure of d(G(4)T(4)G(3))2: a bimolecular G-quadruplex with a novel fold. J. Mol. Biol. 320:911–924. PubMed

Cubero, E., A. Avino, B. G. de la Torre, M. Frieden, R. Eritja, F. J. Luque, C. Gonzalez, and M. Orozco. 2002. Hoogsteen-based parallel-stranded duplexes of DNA. Effect of 8-amino-purine derivatives. J. Am. Chem. Soc. 124:3133–3142. PubMed

Cubero, E., C. A. Laughton, F. J. Luque, and M. Orozco. 2000. Molecular dynamics study of oligonucleotides containing difluorotoluene. J. Am. Chem. Soc. 122:6891–6899.

Cubero, E., F. J. Luque, and M. Orozco. 2001. Theoretical studies of d(A: T)-based parallel-stranded DNA duplexes. J. Am. Chem. Soc. 123:12018–12025. PubMed

Cui, G. L., and C. Simmerling. 2002. Conformational heterogeneity observed in simulations of a pyrene-substituted DNA. J. Am. Chem. Soc. 124:12154–12164. PubMed

Elber, R., and M. Karplus. 1990. Enhanced sampling in molecular-dynamics: use of the time-dependent Hartree approximation for a simulation of carbon-monoxide diffusion through myoglobin. J. Am. Chem. Soc. 112:9161–9175.

Fadrna, E., and J. Koca. 1997. Single-coordinate-driving method coupled with simulated annealing. An efficient tool to search conformational space. J. Phys. Chem. B. 101:7863–7868.

Fedoroff, O. Y., M. Salazar, H. Y. Han, V. V. Chemeris, S. M. Kerwin, and L. H. Hurley. 1998. NMR-based model of a telomerase-inhibiting compound bound to G-quadruplex DNA. Biochemistry. 37:12367–12374. PubMed

Giudice, E., and R. Lavery. 2002. Simulations of nucleic acids and their complexes. Acc. Chem. Res. 35:350–357. PubMed

Gowan, S. M., J. R. Harrison, L. Patterson, M. Valenti, M. A. Read, S. Neidle, and L. R. Kelland. 2002. A G-quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. Mol. Pharmacol. 61:1154–1162. PubMed

Haider, S., G. N. Parkinson, and S. Neidle. 2002. Crystal structure of the potassium form of an Oxytricha nova G-quadruplex. J. Mol. Biol. 320:189–200. PubMed

Han, H. Y., C. L. Cliff, and L. H. Hurley. 1999. Accelerated assembly of G-quadruplex structures by a small molecule. Biochemistry. 38:6981–6986. PubMed

Hardin, C. C., A. G. Perry, and K. White. 2000. Thermodynamic and kinetic characterization of the dissociation and assembly of quadruplex nucleic acids. Biopolymers. 56:147–194. PubMed

Honig, B., and A. Nicholls. 1995. Classical electrostatics in biology and chemistry. Science. 268:1144–1149. PubMed

Horvath, M. P., and S. C. Schultz. 2001. DNA G-quartets in a 1.86 angstrom resolution structure of an Oxytricha nova telomeric protein-DNA complex. J. Mol. Biol. 310:367–377. PubMed

Hud, N. V., P. Schultze, V. Sklenar, and J. Feigon. 1999. Binding sites and dynamics of ammonium ions in a telomere repeat DNA quadruplex. J. Mol. Biol. 285:233–243. PubMed

Hud, N. V., F. W. Smith, F. A. L. Anet, and J. Feigon. 1996. The selectivity for K+ versus Na+ in DNA quadruplexes is dominated by relative free energies of hydration: a thermodynamic analysis by H-1 NMR. Biochemistry. 35:15383–15390. PubMed

Imberty, A., and S. Perez. 1994. Molecular modeling of protein carbohydrate interactions. Understanding the specificities of two legume lectins towards oligosaccharides. Glycobiology. 4:351–366. PubMed

Jayaram, B., D. Sprous, and D. L. Beveridge. 1998. Solvation free energy of biomacromolecules: parameters for a modified generalized born model consistent with the AMBER force field. J. Phys. Chem. B. 102:9571–9576.

Jorgensen, W. L., J. Chandrasekhar, J. D. Madura, R. W. Impey, and M. L. Klein. 1983. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79:926–935.

Kang, S. G., and E. Henderson. 2002. Identification of non-telomeric G4-DNA binding proteins in human, E. coli, yeast, and Arabidopsis. Mol. Cells. 14:404–410. PubMed

Kang, C., X. H. Zhang, R. Ratliff, R. Moyzis, and A. Rich. 1992. Crystal-structure of four-stranded Oxytricha telomeric DNA. Nature. 356:126–131. PubMed

Koca, J. 1994. Computer-program cicada - traveling along conformational potential-energy hypersurface. J. Mol. Struct. Theochem. 114:13–24.

Kollman, P. A., I. Massova, C. Reyes, B. Kuhn, S. H. Huo, L. Chong, M. Lee, T. Lee, Y. Duan, W. Wang, O. Donini, P. Cieplak, J. Srinivasan, D. A. Case, and T. E. Cheatham. 2000. Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc. Chem. Res. 33:889–897. PubMed

Lankas, F., T. E. Cheatham, N. Spackova, P. Hobza, J. Langowski, and J. Sponer. 2002. Critical effect of the N2 amino group on structure, dynamics, and elasticity of DNA polypurine tracts. Biophys. J. 82:2592–2609. PubMed PMC

MacKerell, A. D., N. Banavali, and N. Foloppe. 2000. Development and current status of the CHARMM force field for nucleic acids. Biopolymers. 56:257–265. PubMed

Marathias, V. M., and P. H. Bolton. 2000. Structures of the potassium-saturated, 2: 1, and intermediate, 1: 1, forms of a quadruplex DNA. Nucleic Acids Res. 28:1969–1977. PubMed PMC

McQuarrie, D. A. 1976. Statistical Mechanics. Harper & Row, New York.

Meyer, M., C. Schneider, M. Brandl, and J. Suhnel. 2001. Cyclic adenine-, cytosine-, thymine-, and mixed guanine-cytosine-base tetrads in nucleic acids viewed from a quantum-chemical and force field perspective. J. Phys. Chem. A. 105:11560–11573.

Mohanty, D., and M. Bansal. 1993. Conformational polymorphism in G-tetraplex structures: strand reversal by base flipover or sugar flipover. Nucleic Acids Res. 21:1767–1774. PubMed PMC

Mohanty, D., and M. Bansal. 1994. Conformational polymorphism in telomeric structures: loop orientation and interloop pairing in D(G(4)T(N)G(4)). Biopolymers. 34:1187–1211. PubMed

Neidle, S., and G. N. Parkinson. 2003. The structure of telomeric DNA. Curr. Opin. Struct. Biol. 13:275–283. PubMed

Neidle, S., and M. A. Read. 2000. G-quadruplexes as therapeutic targets. Biopolymers. 56:195–208. PubMed

Norberg, J., and L. Nilsson. 2002. Molecular dynamics applied to nucleic acids. Acc. Chem. Res. 35:465–472. PubMed

Orozco, M., A. Perez, A. Noy, and F. J. Luque. 2003. Theoretical methods for the simulation of nucleic acids. Chem. Soc. Rev. 32:350–364. PubMed

Parkinson, G. N., M. P. H. Lee, and S. Neidle. 2002. Crystal structure of parallel quadruplexes from human telomeric DNA. Nature. 417:876–880. PubMed

Phan, A. T., and J. L. Mergny. 2002. Human telomeric DNA: G-quadruplex, i-motif and Watson-Crick double helix. Nucleic Acids Res. 30:4618–4625. PubMed PMC

Phillips, K., Z. Dauter, A. I. H. Murchie, D. M. J. Lilley, and B. Luisi. 1997. The crystal structure of a parallel-stranded guanine tetraplex at 0.95 angstrom resolution. J. Mol. Biol. 273:171–182. PubMed

Reblova, K., N. Spackova, R. Stefl, K. Csaszar, J. Koca, N. B. Leontis, and J. Sponer. 2003. Non-Watson-Crick basepairing and hydration in RNA motifs: molecular dynamics of 5S rRNA loop E. Biophys. J. 84:3564–3582. PubMed PMC

Riou, J. F., L. Guittat, P. Mailliet, A. Laoui, E. Renou, O. Petitgenet, F. Megnin-Chanet, C. Helene, and J. L. Mergny. 2002. Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands. Proc. Natl. Acad. Sci. USA. 99:2672–2677. PubMed PMC

Roitberg, A., and R. Elber. 1991. Modeling side-chains in peptides and proteins: application of the locally enhanced sampling and the simulated annealing methods to find minimum energy conformations. J. Chem. Phys. 95:9277–9287.

Ross, W. S., and C. C. Hardin. 1994. Ion-induced stabilization of the G-DNA quadruplex: free-energy perturbation studies. J. Am. Chem. Soc. 116:6070–6080.

Ryckaert, J. P., G. Ciccoti, and H. J. C. Berendsen. 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.

Schaffitzel, C., I. Berger, J. Postberg, J. Hanes, H. J. Lipps, and A. Pluckthun. 2001. In vitro generated antibodies specific for telomeric guanine- quadruplex DNA react with Stylonychia lemnae macronuclei. Proc. Natl. Acad. Sci. USA. 98:8572–8577. PubMed PMC

Schlitter, J. 1993. Estimation of absolute and relative entropies of macromolecules using the covariance-matrix. Chem. Phys. Lett. 215:617–621.

Schultze, P., N. V. Hud, F. W. Smith, and J. Feigon. 1999. The effect of sodium, potassium and ammonium ions on the conformation of the dimeric quadruplex formed by the Oxytricha nova telomere repeat oligonucleotide d(G(4)T(4)G(4)). Nucleic Acids Res. 27:3018–3028. PubMed PMC

Schultze, P., F. W. Smith, and J. Feigon. 1994. Refined solution structure of the dimeric quadruplex formed from the Oxytricha telomeric oligonucleotide d(GGGGTTTTGGGG). Structure. 2:221–233. PubMed

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

Shields, G. C., C. A. Laughton, and M. Orozco. 1997. Molecular dynamics simulations of the d(T·A·T) triple helix. J. Am. Chem. Soc. 119:7463–7469.

Simmerling, C., R. Elber, and J. Zhang. 1995. MOIL-View—a program for visualization of structure and dynamics of biomolecules and STO—a program for computing stochastic paths. In Modeling of Biomolecular Structure and Mechanisms. A Pullman, J. Jortner, and B. Pullman, editors. Kluwer, The Netherlands. 241–265.

Simmerling, C., J. L. Miller, and P. A. Kollman. 1998. Combined locally enhanced sampling and particle mesh Ewald as a strategy to locate the experimental structure of a nonhelical nucleic acid. J. Am. Chem. Soc. 120:7149–7155.

Sitkoff, D., K. A. Sharp, and B. Honig. 1994. Accurate calculation of hydration free-energies using macroscopic solvent models. J. Phys. Chem. 98:1978–1988.

Smirnov, I., and R. H. Shafer. 2000. Effect of loop sequence and size on DNA aptamer stability. Biochemistry. 39:1462–1468. PubMed

Smith, F. W., and J. Feigon. 1992. Quadruplex structure of Oxytricha telomeric DNA oligonucleotides. Nature. 356:164–168. PubMed

Smith, F. W., P. Schultze, and J. Feigon. 1995. Solution structures of unimolecular quadruplexes formed by oligonucleotides containing Oxytricha telomere repeats. Structure. 3:997–1008. PubMed

Spackova, N., I. Berger, and J. Sponer. 1999. Nanosecond molecular dynamics simulations of parallel and antiparallel guanine quadruplex DNA molecules. J. Am. Chem. Soc. 121:5519–5534.

Spackova, N., I. Berger, and J. Sponer. 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. PubMed

Srinivasan, J., T. E. Cheatham, P. Cieplak, P. A. Kollman, and D. A. Case. 1998. Continuum solvent studies of the stability of DNA, RNA, and phosphoramidate-DNA helices. J. Am. Chem. Soc. 120:9401–9409.

Stefl, R., T. E. Cheatham, N. Spackova, E. Fadrna, I. Berger, J. Koca, and J. Sponer. 2003. Formation pathways of a guanine-quadruplex DNA revealed by molecular dynamics and thermodynamic analysis of the substates. Biophys. J. 85:1787–1804. PubMed PMC

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

Strahan, G. D., M. A. Keniry, and R. H. Shafer. 1998. NMR structure refinement and dynamics of the K+-d(G(3)T(4)G(3)) (2) quadruplex via particle mesh Ewald molecular dynamics simulations. Biophys. J. 75:968–981. PubMed PMC

Strahs, D., and T. Schlick. 2000. A-tract bending: insights into experimental structures by computational models. J. Mol. Biol. 301:643–663. PubMed

Suhnel, J. 2001. Beyond nucleic acid base pairs: from triads to heptads. Biopolymers. 61:32–51. PubMed

Varnai, P., and R. Lavery. 2002. Base flipping in DNA: pathways and energetics studied with molecular dynamic simulations. J. Am. Chem. Soc. 124:7272–7273. PubMed

Wang, Y., and D. J. Patel. 1992. Guanine residues in D(T2ag3) and D(T2g4) form parallel-stranded potassium cation stabilized G-quadruplexes with antiglycosidic torsion angles in solution. Biochemistry. 31:8112–8119. PubMed

Williamson, J. R., M. K. Raghuraman, and T. R. Cech. 1989. Monovalent cation induced structure of telomeric DNA: the G-quartet model. Cell. 59:871–880. PubMed

Yang, L. Q., and B. M. Pettitt. 1996. B to A transition of DNA on the nanosecond time scale. J. Phys. Chem. 100:2564–2566.

Young, M. A., and D. L. Beveridge. 1998. Molecular dynamics simulations of an oligonucleotide duplex with adenine tracts phased by a full helix turn. J. Mol. Biol. 281:675–687. PubMed

Young, M. A., G. Ravishanker, and D. L. Beveridge. 1997. A 5-nanosecond molecular dynamics trajectory for B-DNA: analysis of structure, motions, and solvation. Biophys. J. 73:2313–2336. PubMed PMC

Zacharias, M. 2000. Simulation of the structure and dynamics of nonhelical RNA motifs. Curr. Opin. Struct. Biol. 10:311–317. PubMed

Exploring the Dynamics of Propeller Loops in Human Telomeric DNA Quadruplexes Using Atomistic Simulations

Extended molecular dynamics of a c-kit promoter quadruplex

Structural dynamics of possible late-stage intermediates in folding of quadruplex DNA studied by molecular simulations

Toward Improved Description of DNA Backbone: Revisiting Epsilon and Zeta Torsion Force Field Parameters

Reference simulations of noncanonical nucleic acids with different χ variants of the AMBER force field: quadruplex DNA, quadruplex RNA and Z-DNA

Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures

Performance of Molecular Mechanics Force Fields for RNA Simulations: Stability of UUCG and GNRA Hairpins

Molecular dynamics simulations suggest that RNA three-way junctions can act as flexible RNA structural elements in the ribosome

Extensive molecular dynamics simulations showing that canonical G8 and protonated A38H+ forms are most consistent with crystal structures of hairpin ribozyme

An RNA molecular switch: Intrinsic flexibility of 23S rRNA Helices 40 and 68 5'-UAA/5'-GAN internal loops studied by molecular dynamics methods

Theoretical studies of RNA catalysis: hybrid QM/MM methods and their comparison with MD and QM

Conformations of flanking bases in HIV-1 RNA DIS kissing complexes studied by molecular dynamics

Molecular dynamics simulations and their application to four-stranded DNA

Cations and hydration in catalytic RNA: molecular dynamics of the hepatitis delta virus ribozyme