A virtual library of constrained cyclic tetrapeptides that mimics all four side-chain orientations for over half the reverse turns in the protein data bank

Article

Abstract

Reverse turns are often recognition sites for protein/protein interactions and, therefore, valuable potential targets for determining recognition motifs in development of potential therapeutics. A virtual combinatorial library of cyclic tetrapeptides (CTPs) was generated and the bonds in the low-energy structures were overlapped with canonical reverse-turn Cα–Cβ bonds (Tran et al., J Comput Aided Mol Des 19(8):551–566, 2005) to determine the utility of CTPs as reverse-turn peptidomimetics. All reverse turns in the Protein Data Bank (PDB) with a crystal structures resolution ≤3.0 Å were classified into the same known canonical reverse-turn Cα–Cβ bond clusters (Tran et al., J Comput Aided Mol Des 19(8):551–566, 2005). CTP reverse-turn mimics were compiled that mimicked both the relative orientations of three of the four as well as all four Cα–Cβ bonds in the reverse turns of the PDB. 54% of reverse turns represented in the PDB had eight or more CTPs structures that mimicked the orientation of all four of the Cα–Cβ bonds in the reverse turn.

Keywords

Cyclic tetrapeptide Reverse turn Mimic Conformational search 

Notes

Acknowledgements

This work was funded in part by NIH Grant GM 68460. Sage Arbor acknowledges fellowship support from the Division of Biology and Biological Sciences, Washington University in St. Louis, Kauffman Cancer Research Pathway, and Washington University Center for Computational Biology Pathway.

References

  1. 1.
    Fairlie DP, West ML, Wong AK (1998) Towards protein surface mimetics. Curr Med Chem 5(1):29–62Google Scholar
  2. 2.
    Tyndall JD, Pfeiffer B, Abbenante G, Fairlie DP (2005) Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure. Chem Rev 105(3):793–826CrossRefGoogle Scholar
  3. 3.
    Li R, Hoess RH, Bennett JS, DeGrado WF (2003) Use of phage display to probe the evolution of binding specificity and affinity in integrins. Protein Eng 16(1):65–72CrossRefGoogle Scholar
  4. 4.
    Hanessian S, McNaughtonsmith G, Lombart HG, Lubell WD (1997) Design and synthesis of conformationally constrained amino acids as versatile scaffolds and peptide mimetics. Tetrahedron 53(38):12789–12854CrossRefGoogle Scholar
  5. 5.
    Marraud M, Aubry A (1996) Crystal structures of peptides and modified peptides [Review]. Biopolymers 40(1):45–83CrossRefGoogle Scholar
  6. 6.
    Karle IL, Awasthi SK, Balaram P (1996) A designed beta-hairpin peptide in crystals. Proc Natl Acad Sci USA 93(16):8189–8193CrossRefGoogle Scholar
  7. 7.
    Arbor SK, Kao J, Yun W, Marshall G (2007) c[d-pro-Pro-d-pro-N-methyl-Ala] adopts a rigid conformation that serves as a scaffold to mimic reverse-turn. Biopolym Peptide Sci (in press)Google Scholar
  8. 8.
    Rose GD, Gierasch LM, Smith JA (1985) Turns in peptides and proteins. Adv Protein Chem 37:1–109CrossRefGoogle Scholar
  9. 9.
    Ripka WC, DeLucca GV, Bach AC II, Pottorf RS, Blaney JM (1993) Protein β-turn mimetics I: design, synthesis, and evaluation in model cyclic peptides. Tetrahedron 49(17):3593–3608CrossRefGoogle Scholar
  10. 10.
    Muller G, Gurrath M, Kurz M, Kessler H (1993) Beta VI turns in peptides and proteins: a model peptide mimicry. Proteins 15(3):235–251CrossRefGoogle Scholar
  11. 11.
    Reaka AJ, Ho CM, Marshall GR (2002) Metal complexes of chiral pentaazacrowns as conformational templates for beta-turn recognition. J Comput Aided Mol Des 16(8–9):585–600CrossRefGoogle Scholar
  12. 12.
    Bunin B, Plunkett M, Ellman J (1994) The combinatorial synthesis and chemical and biological evaluation of a 1,4-benzodiazapine library. Proc Natl Acad Sci USA 91:4708–4712CrossRefGoogle Scholar
  13. 13.
    Ripka WC, Lucca GVD, Bach ACII, Pottorf RS, Blaney JM (1993) Protein β-turn mimetics II: design, synthesis, and evaluation in the cyclic peptide gramicidin S. Tetrahedron 49(17):3609–3628CrossRefGoogle Scholar
  14. 14.
    Horton DA, Bourne GT, Smythe ML (2003) The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem Rev 103(3):893–930CrossRefGoogle Scholar
  15. 15.
    Breinbauer R, Vetter IR, Waldmann H (2002) From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem Int Ed Engl 41(16):2879–2890CrossRefGoogle Scholar
  16. 16.
    Muller G (2003) Medicinal chemistry of target family-directed masterkeys. Drug Discov Today 8(15):681–691CrossRefGoogle Scholar
  17. 17.
    Baca M, Alewood PF, Kent SB (1993) Structural engineering of the HIV–1 protease molecule with a beta-turn mimic of fixed geometry. Protein Sci 2(7):1085–1091CrossRefGoogle Scholar
  18. 18.
    Blomberg D (2007) Synthesis of β-turn and pyridine based peptidomimetics. Intellecta DocuSys, Västra FrölundaGoogle Scholar
  19. 19.
    Palomo C, Aizpurua JM, Balentova E, Jimenez A, Oyarbide J, Fratila RM, Miranda JI (2007) Synthesis of beta-lactam scaffolds for ditopic peptidomimetics. Org Lett 9(1):101–104CrossRefGoogle Scholar
  20. 20.
    Martin-Martinez M, De la Figuera N, Latorre M, Garcia-Lopez MT, Cenarruzabeitia E, Del Rio J, Gonzalez-Muniz R (2005) Conformationally constrained CCK4 analogues incorporating IBTM and BTD beta-turn mimetics. J Med Chem 48(24):7667–7674CrossRefGoogle Scholar
  21. 21.
    Chalmers DK, Marshall GR (1995) Pro-d-NMe-amino acid and d-Pro-NMe-amino acid: simple, efficient reverse-turn constraints. J Am Chem Soc 117:5927–5937CrossRefGoogle Scholar
  22. 22.
    Takeuchi Y, Marshall GR (1998) Conformational analysis of reverse-turn constraints by N-methylation and N-hydroxylation of amide bonds in peptides and non-peptide mimetics. J Am Chem Soc 120(22):5363–5372CrossRefGoogle Scholar
  23. 23.
    Spath J, Stuart F, Jiang L, Robinson JA (1998) Stabilization of a β-hairpin conformation in a cyclic peptide using the templating effect of a heterochiral diproline unit. Helv Chim Acta 81:1726–1738CrossRefGoogle Scholar
  24. 24.
    Che Y, Marshall GR (2006) Engineering cyclic tetrapeptides containing chimeric amino acids as preferred reverse-turn scaffolds. J Med Chem 49(1):111–124CrossRefGoogle Scholar
  25. 25.
    Rizo J, Gierasch LM (1992) Constrained peptides: models of bioactive peptides and protein substructures. Annu Rev Biochem 61:387–418CrossRefGoogle Scholar
  26. 26.
    Tran TT, McKie J, Meutermans WD, Bourne GT, Andrews PR, Smythe M (2005) Topological side-chain classification of beta-turns: ideal motifs for peptidomimetic development. J Comput Aided Mol Des 19(8):551–566CrossRefGoogle Scholar
  27. 27.
    Macromodel 7.2 (2001) Schrodinger, Inc, PortlandGoogle Scholar
  28. 28.
    Chang G, Guida WC, Still WC (1989) An internal coordinate Monte-Carlo method for searching conformational space. J Am Chem Soc 111:4379–4386CrossRefGoogle Scholar
  29. 29.
    Saunders M, Houk KN, Wu Y-D, Still WC, Lipton M, Chang G, Guida WC (1990) Conformations of cycloheptadecane. A comparison of methods for conformational searching. J Am Chem Soc 112(4):1419–1427CrossRefGoogle Scholar
  30. 30.
    Still WC, Tempczyk A, Hawley RC, Hendrickson T (1990) Semianalytical treatment of solvation for molecular mechanics and dynamics. J Am Chem Soc 112(16):6127–6129CrossRefGoogle Scholar
  31. 31.
    Welsh EA (2005) POSSE: a program for the automated pair-wise superposition and alignment of protein structures. Washington University, St. LouisGoogle Scholar
  32. 32.
    The Open Babel Package 2.02 (2006) http://openbabel.sourceforge.net
  33. 33.
    Ho CMW, Marshall GR (1993) FOUNDATION: a program to retrieve subsets of query elements, including active site region accessibility, from three-dimensional databases. J Comput Aided Mol Des 7:3–22CrossRefGoogle Scholar
  34. 34.
    Sybyl 7.3 (2006) Tripos international: 1699 South Hanley Rd., St. Louis, Missouri, 63144, USAGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiophysicsWashington University School of MedicineSt. LouisUSA

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