Structural Chemistry

, Volume 28, Issue 6, pp 1853–1885 | Cite as

Structural characteristics of cyclopentane-modified peptide nucleic acids from molecular dynamics simulations

Original Research
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Abstract

A PNA molecule is a DNA strand where the sugar-phosphate backbone has been replaced by a structurally homomorphous pseudopeptide chain consisting of N (2-amino-ethyl)-glycine units. PNA binds strongly to both DNA and RNA. However, an analysis of the X-ray and NMR data show that the dihedral angles of PNA/DNA or PNA/RNA complexes are very different from those of DNA:DNA or RNA:RNA complexes. In addition, the PNA strand is very flexible. One way to improve the binding affinity of PNA for DNA/RNA is to design a more pre-organized PNA structure. An effective way to rigidify the PNA strand is to introduce ring structures into the backbone. In several experimental studies, the ethylenediamine portion of aminoethyl glycine peptide nucleic acids (aegPNA) has been replaced with one or more (S,S)-trans cyclopentyl (cpPNA) units. This substitution has met with varied success in terms of DNA/RNA recognition. In the present work, molecular modeling studies were performed to a PNA molecule. Detailed investigations on the conformational and dynamical properties of single-stranded aegPNA and cpPNA were undertaken to determine how the cyclopentane ring will improve binding and to determine the contributions of both entropy and dihedral angle preference to the observed stronger binding. The effects of single and multiple modifications of the PNA backbone were also analyzed to understand changes in conformational and dynamical properties.

Keywords

Peptide nucleic acid Molecular dynamics simulation Conformational dynamics, DNA, RNA 

Notes

Acknowledgments

This research was supported in part by PSC-CUNY research grant (award cycle 47).

Compliance with ethical standards

Conflict of interest

The author declares that she has no conflict of interest.

Supplementary material

11224_2017_970_MOESM1_ESM.docx (203 kb)
ESM 1 (DOCX 203 kb)
11224_2017_970_MOESM2_ESM.docx (8.6 mb)
ESM 2 (DOCX 8762 kb)

References

  1. 1.
    Nielsen PE (2010) Chem Biodivers 7:786–804CrossRefGoogle Scholar
  2. 2.
    Corradini R, Sforza S, Tedeschi T, et al (2007) Curr Top Med Chem 7:681–694CrossRefGoogle Scholar
  3. 3.
    Nielsen PE, Egholm M, Berg RH, Buchardt O (1991) Science 254:1497–1500CrossRefGoogle Scholar
  4. 4.
    Maekawa K, Azuma M, Okuno Y, et al (2015) Bioorganic Med Chem 23:7234–7239CrossRefGoogle Scholar
  5. 5.
    Bertucci A, Prasetyanto EA, Septiadi D, et al (2015) Small 11:5687–5695CrossRefGoogle Scholar
  6. 6.
    Cai B, Huang L, Zhang H, et al (2015) Biosens Bioelectron 74:329–334CrossRefGoogle Scholar
  7. 7.
    Belotserkovskii BP, Hanawalt PC (2015) Mol Carcinog 54:1508–1512CrossRefGoogle Scholar
  8. 8.
    Egholm M, Buchardt O, Christensen L, et al (1993) Nature 365:566–568CrossRefGoogle Scholar
  9. 9.
    Weiler J, Gausepohl H, Hauser N, et al (1997) Nucleic Acids Res 25:2792–2799CrossRefGoogle Scholar
  10. 10.
    Dezhenkov AV, Tankevich MV, Nikolskaya ED, et al (2015) Mendeleev Commun 25:47–48CrossRefGoogle Scholar
  11. 11.
    Pokharel D, Fueangfung S, Zhang M, Fang S (2014) In: Biopolym. - Pept. Sci. Sect. pp 487–493Google Scholar
  12. 12.
    Igloi GL (1998) Proc Natl Acad Sci U S A 95:8562–8567CrossRefGoogle Scholar
  13. 13.
    Brown SC, Thomson SA, Veal JM, Davis DG (1994) Science 265:777–780CrossRefGoogle Scholar
  14. 14.
    Eriksson M, Nielsen PE (1996) Nat Struct Biol 3:410–413CrossRefGoogle Scholar
  15. 15.
    Betts L, Josey JA, Veal JM, Jordan SR (1995) Science 270:1838–1841CrossRefGoogle Scholar
  16. 16.
    Sen S, Nilsson L (2001) J Am Chem Soc 123:7414–7422CrossRefGoogle Scholar
  17. 17.
    Soliva R, Sherer E, Luque FJ, et al (2000) J Am Chem Soc 122:5997–6008CrossRefGoogle Scholar
  18. 18.
    Autiero I, Saviano M, Langella E (2014) Phys Chem Chem Phys 16:1868–1874CrossRefGoogle Scholar
  19. 19.
    Autiero I, Saviano M, Langella E (2015) Eur J Med Chem 91:109–117CrossRefGoogle Scholar
  20. 20.
    Kumar VA, Ganesh KN (2005) Acc Chem Res 38:404–412CrossRefGoogle Scholar
  21. 21.
    Govindaraju T, Kumar VA, Ganesh KN (2004) J Org Chem 69:5725–5734CrossRefGoogle Scholar
  22. 22.
    Pokorski JK, Witschi MA, Purnell BL, Appella DH (2004) J Am Chem Soc 126:15067–15073CrossRefGoogle Scholar
  23. 23.
    Myers MC, Witschi MA, Larionova NV, et al (2003) Org Lett 5:2695–2698CrossRefGoogle Scholar
  24. 24.
    Govindaraju T, Kumar VA, Ganesh KN (2004) J Org Chem 69:1858–1865CrossRefGoogle Scholar
  25. 25.
    Sharma S, Sonavane UB, Joshi RR (2009) Int J Quantum Chem 109:890–896CrossRefGoogle Scholar
  26. 26.
    Pokorski JK, Nam J-M, Vega RA, et al (2005) Chem Commun 2005:2101–2103CrossRefGoogle Scholar
  27. 27.
    Pokorski JK, Myers MC, Appella DH (2005) Tetrahedron Lett 46:915–917CrossRefGoogle Scholar
  28. 28.
    Englund EA, Appella DH (2005) Org Lett 7:3465–3467CrossRefGoogle Scholar
  29. 29.
    B P. Gangamani, V A. Kumar, K N. Ganesh (1997) Chem Commun 1913.Google Scholar
  30. 30.
    Govindaraju T, Kumar V (2005) Chem Commun (Camb) 495–497.Google Scholar
  31. 31.
    Govindaraju T, Kumar VA (2006) Tetrahedron 62:2321–2330CrossRefGoogle Scholar
  32. 32.
    Kumar VA (2002) European J Org Chem 2002:2021–2032CrossRefGoogle Scholar
  33. 33.
    Gangamani BP, Kumar VA, Ganesh KN (1996) Tetrahedron 52:15017–15030CrossRefGoogle Scholar
  34. 34.
    D’Costa M, Kumar VA, Ganesh KN (1999) Org Lett 1:1513–1516CrossRefGoogle Scholar
  35. 35.
    D’Costa M, Kumar V, Ganesh KN (2001) Org Lett 3:1281–1284CrossRefGoogle Scholar
  36. 36.
    Kumar V, Pallan PS, Meena, Ganesh KN (2001) Org Lett 3:1269–1272CrossRefGoogle Scholar
  37. 37.
    Lonkar PS, Kumar VA (2004) Bioorganic Med Chem Lett 14:2147–2149CrossRefGoogle Scholar
  38. 38.
    Govindaraju T, Kumar VA, Ganesh KN (2004) Chem Commun 1:860–861CrossRefGoogle Scholar
  39. 39.
    Feriotto G, Corradini R, Sforza S, et al (2001) Lab Investig 81:1415–1427CrossRefGoogle Scholar
  40. 40.
    Corradini R, Feriotto G, Sforza S, et al (2004) J Mol Recognit 17:76–84CrossRefGoogle Scholar
  41. 41.
    Wittung P, Nielsen PE, Buchardt O, et al (1994) Nature 368:561–563CrossRefGoogle Scholar
  42. 42.
    Wittung P, Eriksson M, Lyng R, et al (1995) J Am Chem Soc 117:10167–10173CrossRefGoogle Scholar
  43. 43.
    Jain V, Green M, Faccini A, et al (2006) Polym Prepr 26–27.Google Scholar
  44. 44.
    Brooks BR, Iii CLB, Mackerell AD, et al (2009) J Comput Chem 30:1545–1614CrossRefGoogle Scholar
  45. 45.
    Manukyan AK (2015) Theor Chem Accounts:134Google Scholar
  46. 46.
    Jorgensen WL, Chandrasekhar J, Madura JD, et al (1983) J Chem Phys 79:926–935CrossRefGoogle Scholar
  47. 47.
    Rasmussen H, Kastrup JS, Nielsen JN, et al (1997) Nat Struct Biol 4:98–101CrossRefGoogle Scholar
  48. 48.
    Menchise V, De Simone G, Tedeschi T, et al (2003) Proc Natl Acad Sci U S A 100:12021–12026CrossRefGoogle Scholar
  49. 49.
    Perbandt M, Vallazza M, Lippmann C, et al (2001) Acta Crystallogr Sect D Biol Crystallogr 57:219–224CrossRefGoogle Scholar
  50. 50.
    Leporc S, Mauffret O, Tevanian G, et al (1999) Nucleic Acids Res 27:4759–4767CrossRefGoogle Scholar
  51. 51.
    Berman H (1997) Biopolymers 44:23CrossRefGoogle Scholar
  52. 52.
    Shishkin OV, Pelmenschikov A, Hovorun DM, Leszczynski J (2000) J Mol Struct 526:329–341CrossRefGoogle Scholar
  53. 53.
    Yurenko YP, Zhurakivsky RO, Ghomi M, Samijlenko SP, Hovorun DM (2008) J Chem Phys 112:1240–1250CrossRefGoogle Scholar
  54. 54.
    Yurenko YP, Zhurakivsky RO, Samijlenko SP, Hovorun DM, Frank-Kamenteskii M (2012) J Biomol Struct Dyn 29(1):51–65CrossRefGoogle Scholar
  55. 55.
    Brovarets’ OO, Yurenko YP, Hovorun DM (2015) J Biomol Struct Dyn 33(8):1624–1652CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Natural SciencesCUNY Hostos Community CollegeBronxUSA

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