Refinement of the AMBER force field for nucleic acids: improving the description of alpha/gamma conformers.
Journal: 2007/September - Biophysical Journal
ISSN: 0006-3495
Abstract:
We present here the parmbsc0 force field, a refinement of the AMBER parm99 force field, where emphasis has been made on the correct representation of the alpha/gamma concerted rotation in nucleic acids (NAs). The modified force field corrects overpopulations of the alpha/gamma = (g+,t) backbone that were seen in long (more than 10 ns) simulations with previous AMBER parameter sets (parm94-99). The force field has been derived by fitting to high-level quantum mechanical data and verified by comparison with very high-level quantum mechanical calculations and by a very extensive comparison between simulations and experimental data. The set of validation simulations includes two of the longest trajectories published to date for the DNA duplex (200 ns each) and the largest variety of NA structures studied to date (15 different NA families and 97 individual structures). The total simulation time used to validate the force field includes near 1 mus of state-of-the-art molecular dynamics simulations in aqueous solution.
Relations:
Content
Citations
(504)
References
(40)
Chemicals
(1)
Processes
(1)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Biophys J 92(11): 3817-3829

Refinement of the AMBER Force Field for Nucleic Acids: Improving the Description of <em>α</em>/<em>γ</em> Conformers

Molecular Modeling and Bioinformatics Unit, Institut de Recerca Biomèdica &amp; Instituto Nacional de Bioinformática, Parc Científic de Barcelona, Barcelona 08028, Spain; Computational Biology Program, Barcelona Supercomputer Centre, Edifici Torre Girona, Barcelona 08028, Spain; Institute of Organic Chemistry and Biochemistry, Center for Biomolecules and Complex Molecular Systems, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic; Institute of Biophysics, Academy of Sciences of the Czech Republic, 612 65 Brno, Czech Republic; Faculty of Science, Masaryk University, 611 37 Brno, Czech Republic; Departments of Medicinal Chemistry, Pharmaceutical Chemistry and Pharmaceutics and Bioengineering, University of Utah, Salt Lake City, Utah 84112; School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom; and Departament de Bioquímica i Biología Molecular, Facultat de Biología, Universitat de Barcelona, Barcelona 08028, Spain
Address reprint request to Modesto Orozco, Molecular Modeling and Bioinformatics Unit, Institut de Recerca Biomèdica &amp; Instituto Nacional de Bioinformática, Parc Científic de Barcelona, Barcelona 08028, Spain. E-mail: se.bu.bcp.bmm@otsedom or se.csb@oczoro.otsedom.
Address reprint request to Modesto Orozco, Molecular Modeling and Bioinformatics Unit, Institut de Recerca Biomèdica &amp; Instituto Nacional de Bioinformática, Parc Científic de Barcelona, Barcelona 08028, Spain. E-mail: se.bu.bcp.bmm@otsedom or se.csb@oczoro.otsedom.
Received 2006 Sep 19; Accepted 2007 Feb 5.

Abstract

We present here the parmbsc0 force field, a refinement of the AMBER parm99 force field, where emphasis has been made on the correct representation of the α/γ concerted rotation in nucleic acids (NAs). The modified force field corrects overpopulations of the α/γ = (g+,t) backbone that were seen in long (more than 10 ns) simulations with previous AMBER parameter sets (parm94-99). The force field has been derived by fitting to high-level quantum mechanical data and verified by comparison with very high-level quantum mechanical calculations and by a very extensive comparison between simulations and experimental data. The set of validation simulations includes two of the longest trajectories published to date for the DNA duplex (200 ns each) and the largest variety of NA structures studied to date (15 different NA families and 97 individual structures). The total simulation time used to validate the force field includes near 1 μs of state-of-the-art molecular dynamics simulations in aqueous solution.

Abstract

APS, antiparallel; PS, parallel-stranded.

Possible transitions are: A, A-DNA conformation; B, B-DNA conformation; Pathol., structure severely distorted due to high number of alpha/gamma (g+/t) substates.

Top entries correspond to the energy minima in the QM maps, and those at the bottom to geometries reoptimized at the quoted level of theory. The pathological gt conformation is not a minimum, and optimization drives geometry out of the region.

Vn/2 are in kcal/mol, and phase angles in degrees. For atom description see Fig. 1. Van der Waals and bond and angle parameters involving the new CI atom are taken from equivalent ones in parm99. A library file containing all parameters is accessible from http://mmb.pcb.ub.es/PARMBSC0. Note that we use standard nomenclature in AMBER datafile, where a negative value of periodicity means that additional Fourier terms for the dihedral will follow. Values in bold are those that were parameterized here under the restraint imposed by the other parameters transferred from standard parm99.

Rotational parameters are in degrees, and distances in Å. The canonical gg is defined in regions of α 240–360° and γ 0–120°. North is defined by phase angles smaller than 90°.

No detailed NMR analysis of sugar puckering is provided in DD structures deposited in PDB. Accurate estimates for a related sequence suggest an average South population around 81%, with more purines than pyrimidines in the South conformations (see text for details).

End bases are excluded from the study and the percentage of maintenance of hydrogen bonds is presented into blocks: canonical Watson-Crick pairs and noncanonical pairs.

Translational parameters are in angstroms, and rotations in degrees. Values in parentheses correspond to experimental values (PDB entries: 352D and 156D for ps and aps G-DNA (loops excluded in the calculations); 135D and 149D for aps and ps triplexes (backbone atoms), Arnott's values for Z-DNA and 1GQU for the aps Hoogsteen duplex.

The values after the slash correspond to those obtained experimentally in aqueous solution by NMR techniques (pdb code: 1efs).

Acknowledgments

We are grateful to Dr. Peter Varnai for kindly providing us the coordinates of his simulation of distorted B-DNA duplex and to Prof. F. Javier Luque for valuable comments and critical reading of this article. We also thank the technical personnel of the Barcelona Supercomputer Center, especially those managing Mare Nostrum for making the massive simulations reported here possible.

This work has been supported by the Spanish Ministry of Education and Science (BIO2006-01602) and Fundación La Caixa. Further support was obtained by grants LC06030 and LC512 and by Research Project Z4 055 905 by Ministry of Education of the Czech Republic. The Nottingham database simulations were made possible by the UK National Grid Service and the University of Nottingham's High Performance Computing Resource. We acknowledge additional computer power provided by Brno and Pittsburgh Supercomputer Centers. A.P. and I.M. are fellows of the Catalan and Spanish Ministries of Education and Science, respectively.

Acknowledgments

Notes

A. Pérez and I. Marchán contributed equally to this work.

Notes
A. Pérez and I. Marchán contributed equally to this work.

References

  • 1. McCammon, J. A. 1976. Models for Protein Dynamics. H. J. C. Berendsen, editor. CECAM - Universite de Paris IX, Orsay (France).
  • 2. McCammon, J. A., B. R. Gelin, and M. Karplus. 1977. Dynamics of folded proteins. Nature.267:585–590. [[PubMed]
  • 3. Levitt, M. 1983. Computer simulation of DNA double-helix dynamics. Cold Spring Harb. Symp. Quant. Biol.47:251–262. [[PubMed]
  • 4. Tidor, B., K. K. Irikura, B. R. Brooks, and M. Karplus. 1983. Dynamics of DNA oligomers. J. Biomol. Struct. Dyn.1:231–252. [[PubMed]
  • 5. Darden, T., D. York, and L. G. Pedersen. 1993. Particle mesh Ewald: An N-log(N) method for Ewald sums in large systems. J. Chem. Phys.98:10089–10092. [PubMed]
  • 6. Cornell, W. D., P. Cieplak, C. I. Baily, I. R. Gould, K. M. Merz, Jr., D. C. Ferguson, T. Fox, J. W. Caldwell, and P. A. Kollman. 1995. A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J. Am. Chem. Soc.117:5179–5197. [PubMed]
  • 7. MacKerell, A. D., J. Wiorkiewicz-Kuczera, and M. Karplus. 1995. An all-atom empirical energy function for the simulation of nucleic acids. J. Am. Chem. Soc.117:11946–11975. [PubMed]
  • 8. Foloppe, N., and A. D. Mackerell. 2000. All-atom empirical force field for nucleic acids: I. Parameter optimization based on small molecule and condensed phase macromolecular target data. J. Comput. Chem.21:86–104. [PubMed]
  • 9. Langley, D. R. 1998. Molecular dynamic simulations of environment and sequence dependent DNA conformations: the development of the BMS nucleic acid force field and comparison with experimental results. J. Biomol. Struct. Dyn.16:487–509. [[PubMed]
  • 10. Cheatham, T. E., III, 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]
  • 11. Cheatham, T. E., III, 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. [PubMed]
  • 12. York, D. M., W. Yang, H. Lee, T. Darden, and L. G. Pedersen. 1995. Toward the accurate modeling of DNA: the importance of long-range electrostatics. J. Am. Chem. Soc.117:5001–5002. [PubMed]
  • 13. Beveridge, D. L., and K. J. McConnell. 2000. Nucleic acids: theory and computer simulation, Y2K. Curr. Opin. Struct. Biol.10:182–196. [[PubMed]
  • 14. Cheatham, T. E., III, and P. A. Kollman. 2000. Molecular dynamics simulation of nucleic acids. Annu. Rev. Struct. Dyn.51:435–471. [[PubMed]
  • 15. Cheatham, T. E., III 2004. Simulation and modeling of nucleic acid structure, dynamics and interactions. Curr. Opin. Struct. Biol.14:360–367. [[PubMed]
  • 16. Giudice, E., and R. Lavery. 2002. Simulations of nucleic acids and their complexes. Acc. Chem. Res.35:350–357. [[PubMed]
  • 17. Orozco, M., A. Pérez, A. Noy, and F. J. Luque. 2003. Theoretical methods for the simulation of nucleic acids. Chem. Soc. Rev.32:350–364. [[PubMed]
  • 18. Orozco, M., M. Rueda, J. R. Blas, E. Cubero, F. J. Luque, and C. A. Laughton. 2004. Encyclopedia of Computational Chemistry. .[PubMed]
  • 19. Pérez, A., J. R. Blas, M. Rueda, J. M. López-Bes, X. de la Cruz, and M. Orozco. 2005. Exploring the essential dynamics of B.DNA. J. Chem. Theor. Comput.1:790–800. [[PubMed]
  • 20. Cheatham III, T. E., and M. A. Young. 2000. Molecular dynamics simulation of nucleic acids: successes, limitations, and promise. Biopolymers.56:232–256. [[PubMed]
  • 21. Cheatham III, T. E., and P. A. Kollman. 1996. Observation of the A-DNA to B-DNA transition during unrestrained molecular dynamics in aqueous solution. J. Mol. Biol.259:434–444. [[PubMed]
  • 22. Soliva, R., F. J. Luque, C. Alhambra, and M. Orozco. 1999. Role of sugar re-puckering in the transition of A and B forms of DNA in solution. A molecular dynamics study. J. Biomol. Struct. Dyn.17:89–99. [[PubMed]
  • 23. Cheatham III, T. E., M. F. Crowley, T. Fox, and P. A. Kollman. 1997. A molecular level picture of the stabilization of A-DNA in mixed ethanol-water solutions. Proc. Natl. Acad. Sci. USA.94:9626–9630.
  • 24. McConnell, K. J., and D. L. Beveridge. 2000. DNA structure: what's in charge? J. Mol. Biol.304:803–820. [[PubMed]
  • 25. Sprous, D., M. A. Young, and D. L. Beveridge. 1998. Molecular dynamics studies of the conformational preferences of a DNA double helix in water and an ethanol/water mixture: Theoretical considerations of the A double left right arrow B transition. J. Phys. Chem. B.102:4658–4667. [PubMed]
  • 26. 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. [PubMed]
  • 27. Cheatham III, T. E., and P. A. Kollman. 1997. Insight into the stabilization of A-DNA by specific ion association: spontaneous B-DNA to A-DNA transitions observed in molecular dynamics simulations of d[ACCCGCGGGT]2 in the presence of hexaamminecobalt(III). Structure (London).5:1297–1311. [[PubMed]
  • 28. Rueda, M., S. G. Kalko, F. J. Luque, and M. Orozco. 2003. The structure and dynamics of DNA in the gas phase. J. Am. Chem. Soc.125:8007–8014. [[PubMed]
  • 29. Rueda, M., F. J. Luque, and M. Orozco. 2005. Nature of minor-groove binders-DNA complexes in the gas phase. J. Am. Chem. Soc.127:11690–11698. [[PubMed]
  • 30. Rueda, M., F. J. Luque, and M. Orozco. 2006. G-quadruplexes can mantain their structure in the gas phase. J. Am. Chem. Soc.128:3608–3619. [[PubMed]
  • 31. Hobza, P., M. Kabelac, J. Sponer, P. Mejzlik, and J. Vondrasek. 1997. Performance of empirical potentials (AMBER, CFF95, CVFF, CHARMM, OPLS, POLTEV), semiempirical quantum chemical methods (AM1, MNDO / M, PM3), and ab initio Hartree-Fock method for interaction of DNA bases: comparison with nonempirical beyond Hartree-Fock results. J. Comp. Chem.18:1136–1150. [PubMed]
  • 32. Alhambra, C., F. J. Luque, F. Gago, and M. Orozco. 1997. Ab initio study of stacking interactions in A- and B-DNA. J. Phys. Chem. B.101:3846–3853. [PubMed]
  • 33. Pérez, A., J. Sponer, P. Jurecka, P. Hobza, F. J. Luque, and M. Orozco. 2005. Are the RNA(A·U) hydrogen bonds stronger than the DNA(A·T) ones? Chem. Eur. J.11:5062–5066. [[PubMed]
  • 34. Sponer, J., P. Jurecka, I. Marchan, F. J. Luque, M. Orozco, and P. Hobza. 2006. Nature of base stacking. Reference quantum chemical stacking energies in ten unique B-DNA base pair steps. Chem. Eur. J.12:2854–2865. [[PubMed]
  • 35. Sponer, J., P. Jurecka, and P. Hobza. 2004. Accurate interaction energies of hydrogen-bonded nucleic acid base pairs. J. Am. Chem. Soc.126:10142–10151. [[PubMed]
  • 36. Sponer, J. E., N. Spackova, J. Leszczynski, and J. Sponer. 2005. Principles of RNA base pairing: structures and energies of the trans Watson-Crick/sugar edge base pairs. J. Phys. Chem. B.109:11399–11410. [[PubMed]
  • 37. Varnai, P., and K. Zakrzewska. 2004. DNA and its counterions: a molecular dynamics study. Nucleic Acids Res.32:4269–4280.
  • 38. Beveridge, D. L., G. Barreiro, K. S. Byun, D. A. Case, T. E. Cheatham III, S. B. Dixit, E. Giudice, F. Lankas, R. Lavery, J. H. Maddocks, R. Osman, E. Seibert, H. Sklenar, G. Stoll, K. M. Thayer, P. Varnai, and M. A. Young. 2004. Molecular dynamics simulations of the 136 unique tetranucleotide sequences of DNA oligonucleotides. I. Research design and results on d(CpG) steps. Biophys. J.87:3799–3813.
  • 39. Dixit, S. B., D. L. Beveridge, D. A. Case, T. E. Cheatham 3rd, E. Giudice, F. Lankas, R. Lavery, J. H. Maddocks, R. Osman, H. Sklenar, K. M. Thayer, and P. Varnai. 2005. Molecular dynamics simulations of the 136 unique tetranucleotide sequences of DNA oligonucleotides. II: Sequence context effects on the dynamical structures of the 10 unique dinucleotide steps. Biophys. J.89:3721–3740.
  • 40. Dixit, S. B., and D. L. Beveridge. 2006. Structural bioinformatics of DNA: a web-based tool for the analysis of molecular dynamics results and structure prediction. Bioinformatics.22:1007–1009. [[PubMed]
  • 41. Saebø, S., and P. Pulay. 1993. Local treatment of electron correlation. Annu. Rev. Phys. Chem.44:213–236. [PubMed]
  • 42. Becke, A. D. 1993. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys.98:5648–5652. [PubMed]
  • 43. Lee, C., W. Yang, and R. G. Parr. 1988. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B.37:785–789. [[PubMed]
  • 44. Barlett, R. J. 1995. Modern Electronic Structure Theory. Part I. D. R. Yarkony, editor. World Science. Singapore.
  • 45. Halkier, A., T. Helgaker, P. Jorgensen, W. Klopper, H. Koch, J. Olsen, and A. K. Wilson. 1998. Basis-set convergence in correlated calculations on Ne, N2 and H2O. Chem. Phys. Lett.286:243–252. [PubMed]
  • 46. Bayly, C. I., P. Cieplak, W. D. Cornell, and P. A. Kollman. 1993. A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges. J. Chem. Phys.97:10269–10280. [PubMed]
  • 47. Dickerson, R. E., and H. L. Ng. 2001. DNA structure from A to B. Proc. Natl. Acad. Sci. USA.98:6986–6988.
  • 48. 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. [PubMed]
  • 49. Shields, G. C., C. A. Laughton, and M. Orozco. 1998. Molecular dynamics simulation of a PNA.DNA.PNA triple helix in aqueous solution. J. Am. Chem. Soc.120:5895–5904. [PubMed]
  • 50. Ryckaert, J. P., G. Ciccotti, and H. J. C. Berendsen. 1977. Numerical-integration of cartesian equations of motion of a system with constraints - molecular-dynamics of N-alkanes. J. Comp. Phys.23:327–341. [PubMed]
  • 51. Ponomarev, S. Y., K. M. Thayer, and D. L. Beveridge. 2004. Ion motions in molecular dynamics simulations on DNA. Proc. Natl. Acad. Sci. USA.101:14771–14775.
  • 52. Isaacs, R. J., and H. P. Spielmann. 2001. NMR evidence for mechanical coupling of phosphate BI-BII transitions with deoxyribose conformational exchange in DNA. J. Mol. Biol.311:149–160. [[PubMed]
  • 53. Pérez, A., A. Noy, F. Lankas, F. J. Luque, and M. Orozco. 2004. The relative flexibility of DNA and RNA: Database analysis. Nucleic Acids Res.32:6144–6151.
  • 54. Krasovska, M. V., J. Sefcikova, K. Reblova, B. Schneider, N. G. Walter, and J. Sponer. 2006. Cations and hydration in catalytic RNA: Molecular dynamics of the hepatitis delta virus ribozyme. Biophys. J.91:626–638.
  • 55. Spackova, N., and J. Sponer. 2006. Molecular dynamics simulations of sarcin-rich rRNA motif. Nucleic Acids Res.34:697–708.
  • 56. Soliva, R., E. Sherer, F. J. Luque, C. A. Laughton, and M. Orozco. 2000. DNA-triplex stabilizing properties of 8-aminoguanine. J. Am. Chem. Soc.122:5997–6008. [PubMed]
  • 57. Cubero, E., N. G. Abrescia, J. A. Subirana, F. J. Luque, C. A. Laughton, and M. Orozco. 2003. J. Am. Chem. Soc.125:14603–14612. [[PubMed]
  • 58. Abrescia, N. G., A. Thompson, T. Huynh-Dinh, and J. A. Subirana. 2002. Proc. Natl. Acad. Sci. USA.99:2806–2811.
  • 59. Lane, A. N., S. Ebel, and T. Brown. 1993. NMR assignments and solution conformation of the DNA.RNA hybrid duplex d(GTGAACTT)· r(AAGUUCAC). Eur. J. Biochem.215:297–306. [[PubMed]
  • 60. Gonzalez, C., W. Stec, M. A. Reynolds, and T. L. James. 1995. Structure and dynamics of a DNA.RNA hybrid duplex with a chiral phosphorothioate moiety: NMR and molecular dynamics with conventional and time-averaged restraints. Biochemistry.34:4969–4982. [[PubMed]
  • 61. Gyi, J. I., D. Gao, G. L. Conn, J. O. Trent, T. Brown, and A. N. Lane. 2003. The solution structure of a DNA.RNA duplex containing 5-propynyl U and C; comparison with 5-Me modifications. Nucleic Acids Res.31:2683–2693.
  • 62. Noy, A., A. Pérez, M. Márquez, F. J. Luque, and M. Orozco. 2005. Structure, recognition properties and flexibility of the DNA·RNA hybrid. J. Am. Chem. Soc.127:4901–4920. [[PubMed]
  • 63. Cheatham, T. E., III, and P. A. Kollman. 1997. Molecular dynamics simulations highlight the structural differences among DNA:DNA, RNA:RNA, and DNA. RNA Hybrid Duplexes. J. Am. Chem. Soc.119:4805–4825. [PubMed]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.