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. 1999 Jun;76(6):3192–3205. doi: 10.1016/S0006-3495(99)77471-0

Unrestrained stochastic dynamics simulations of the UUCG tetraloop using an implicit solvation model.

D J Williams 1, K B Hall 1
PMCID: PMC1300288  PMID: 10354444

Abstract

Three unrestrained stochastic dynamics simulations have been carried out on the RNA hairpin GGAC[UUCG] GUCC, using the AMBER94 force field (Cornell et al., 1995. J. Am. Chem. Soc. 117:5179-5197) in MacroModel 5.5 (Mohamadi et al., 1990. J. Comp. Chem. 11:440-467) and either the GB/SA continuum solvation model (Still et al., 1990. J. Am. Chem. Soc. 112:6127-6129) or a linear distance-dependent dielectric (1/R) treatment. The linear distance-dependent treatment results in severe distortion of the nucleic acid structure, restriction of all hydroxyl dihedrals, and collapse of the counterion atmosphere over the course of a 5-ns simulation. An additional vacuum simulation without counterions shows somewhat improved behavior. In contrast, the two GB/SA simulations (1.149 and 3.060 ns in length) give average structures within 1.2 A of the initial NMR structure and in excellent agreement with results of an earlier explicit solvent simulation (Miller and Kollman, 1997. J. Mol. Biol. 270:436-450). In a 3-ns GB/SA simulation starting with the incorrect UUCG tetraloop structure (Cheong et al., 1990. Nature. 346:680-682), this loop conformation converts to the correct loop geometry (Allain and Varani, 1995. J. Mol. Biol. 250:333-353), suggesting enhanced sampling relative to the previous explicit solvent simulation. Thermodynamic effects of 2'-deoxyribose substitutions of loop nucleotides were experimentally determined and are found to correlate with the fraction of time the ribose 2'-OH is hydrogen bonded and the distribution of the hydroxyl dihedral is observed in the GB/SA simulations. The GB/SA simulations thus appear to faithfully represent structural features of the RNA without the computational expense of explicit solvent.

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Selected References

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  1. Allain F. H., Varani G. Structure of the P1 helix from group I self-splicing introns. J Mol Biol. 1995 Jul 14;250(3):333–353. doi: 10.1006/jmbi.1995.0381. [DOI] [PubMed] [Google Scholar]
  2. Auffinger P., Westhof E. Rules governing the orientation of the 2'-hydroxyl group in RNA. J Mol Biol. 1997 Nov 21;274(1):54–63. doi: 10.1006/jmbi.1997.1370. [DOI] [PubMed] [Google Scholar]
  3. Caves L. S., Evanseck J. D., Karplus M. Locally accessible conformations of proteins: multiple molecular dynamics simulations of crambin. Protein Sci. 1998 Mar;7(3):649–666. doi: 10.1002/pro.5560070314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cheatham T. E., 3rd, Kollman P. A. Observation of the A-DNA to B-DNA transition during unrestrained molecular dynamics in aqueous solution. J Mol Biol. 1996 Jun 14;259(3):434–444. doi: 10.1006/jmbi.1996.0330. [DOI] [PubMed] [Google Scholar]
  5. Cheong C., Varani G., Tinoco I., Jr Solution structure of an unusually stable RNA hairpin, 5'GGAC(UUCG)GUCC. Nature. 1990 Aug 16;346(6285):680–682. doi: 10.1038/346680a0. [DOI] [PubMed] [Google Scholar]
  6. Conte M. R., Conn G. L., Brown T., Lane A. N. Hydration of the RNA duplex r(CGCAAAUUUGCG)2 determined by NMR. Nucleic Acids Res. 1996 Oct 1;24(19):3693–3699. doi: 10.1093/nar/24.19.3693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Daggett V., Kollman P. A., Kuntz I. D. Molecular dynamics simulations of small peptides: dependence on dielectric model and pH. Biopolymers. 1991 Feb 15;31(3):285–304. doi: 10.1002/bip.360310304. [DOI] [PubMed] [Google Scholar]
  8. Freier S. M., Albergo D. D., Turner D. H. Solvent effects on the dynamics of (dG-dC)3. Biopolymers. 1983 Apr;22(4):1107–1131. doi: 10.1002/bip.360220408. [DOI] [PubMed] [Google Scholar]
  9. Fritsch V., Ravishanker G., Beveridge D. L., Westhof E. Molecular dynamics simulations of poly(dA).poly(dT): comparisons between implicit and explicit solvent representations. Biopolymers. 1993 Oct;33(10):1537–1552. doi: 10.1002/bip.360331005. [DOI] [PubMed] [Google Scholar]
  10. Hall K. B. Interaction of RNA hairpins with the human U1A N-terminal RNA binding domain. Biochemistry. 1994 Aug 23;33(33):10076–10088. doi: 10.1021/bi00199a035. [DOI] [PubMed] [Google Scholar]
  11. Harvey S. C. Treatment of electrostatic effects in macromolecular modeling. Proteins. 1989;5(1):78–92. doi: 10.1002/prot.340050109. [DOI] [PubMed] [Google Scholar]
  12. Heus H. A., Pardi A. Structural features that give rise to the unusual stability of RNA hairpins containing GNRA loops. Science. 1991 Jul 12;253(5016):191–194. doi: 10.1126/science.1712983. [DOI] [PubMed] [Google Scholar]
  13. Lesnik E. A., Freier S. M. What affects the effect of 2'-alkoxy modifications? 1. Stabilization effect of 2'-methoxy substitutions in uniformly modified DNA oligonucleotides. Biochemistry. 1998 May 12;37(19):6991–6997. doi: 10.1021/bi972995c. [DOI] [PubMed] [Google Scholar]
  14. Mazur J., Jernigan R. L. Distance-dependent dielectric constants and their application to double-helical DNA. Biopolymers. 1991 Nov;31(13):1615–1629. doi: 10.1002/bip.360311316. [DOI] [PubMed] [Google Scholar]
  15. Miller J. L., Kollman P. A. Observation of an A-DNA to B-DNA transition in a nonhelical nucleic acid hairpin molecule using molecular dynamics. Biophys J. 1997 Nov;73(5):2702–2710. doi: 10.1016/S0006-3495(97)78298-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Miller J. L., Kollman P. A. Theoretical studies of an exceptionally stable RNA tetraloop: observation of convergence from an incorrect NMR structure to the correct one using unrestrained molecular dynamics. J Mol Biol. 1997 Jul 18;270(3):436–450. doi: 10.1006/jmbi.1997.1113. [DOI] [PubMed] [Google Scholar]
  17. Pappu R. V., Marshall G. R., Ponder J. W. A potential smoothing algorithm accurately predicts transmembrane helix packing. Nat Struct Biol. 1999 Jan;6(1):50–55. doi: 10.1038/4922. [DOI] [PubMed] [Google Scholar]
  18. Ramstein J., Lavery R. Energetic coupling between DNA bending and base pair opening. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7231–7235. doi: 10.1073/pnas.85.19.7231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sakata T., Hiroaki H., Oda Y., Tanaka T., Ikehara M., Uesugi S. Studies on the structure and stabilizing factor of the CUUCGG hairpin RNA using chemically synthesized oligonucleotides. Nucleic Acids Res. 1990 Jul 11;18(13):3831–3839. doi: 10.1093/nar/18.13.3831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Schaefer M., Bartels C., Karplus M. Solution conformations and thermodynamics of structured peptides: molecular dynamics simulation with an implicit solvation model. J Mol Biol. 1998 Dec 4;284(3):835–848. doi: 10.1006/jmbi.1998.2172. [DOI] [PubMed] [Google Scholar]
  21. Schreiber H., Steinhauser O. Cutoff size does strongly influence molecular dynamics results on solvated polypeptides. Biochemistry. 1992 Jun 30;31(25):5856–5860. doi: 10.1021/bi00140a022. [DOI] [PubMed] [Google Scholar]
  22. Singh S. B., Kollman P. A. Understanding the thermodynamic stability of an RNA hairpin and its mutant. Biophys J. 1996 Apr;70(4):1940–1948. doi: 10.1016/S0006-3495(96)79758-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Soman K. V., Karimi A., Case D. A. Molecular dynamics analysis of a ribonuclease C-peptide analogue. Biopolymers. 1993 Oct;33(10):1567–1580. doi: 10.1002/bip.360331007. [DOI] [PubMed] [Google Scholar]
  24. Tuerk C., Gauss P., Thermes C., Groebe D. R., Gayle M., Guild N., Stormo G., d'Aubenton-Carafa Y., Uhlenbeck O. C., Tinoco I., Jr CUUCGG hairpins: extraordinarily stable RNA secondary structures associated with various biochemical processes. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1364–1368. doi: 10.1073/pnas.85.5.1364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Varani G., Cheong C., Tinoco I., Jr Structure of an unusually stable RNA hairpin. Biochemistry. 1991 Apr 2;30(13):3280–3289. doi: 10.1021/bi00227a016. [DOI] [PubMed] [Google Scholar]
  26. Woese C. R., Winker S., Gutell R. R. Architecture of ribosomal RNA: constraints on the sequence of "tetra-loops". Proc Natl Acad Sci U S A. 1990 Nov;87(21):8467–8471. doi: 10.1073/pnas.87.21.8467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Young M. A., Ravishanker G., Beveridge D. L. A 5-nanosecond molecular dynamics trajectory for B-DNA: analysis of structure, motions, and solvation. Biophys J. 1997 Nov;73(5):2313–2336. doi: 10.1016/S0006-3495(97)78263-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

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