Journal of Thermal Analysis and Calorimetry

, Volume 127, Issue 2, pp 1491–1499 | Cite as

Cyclodextrin–protein interaction as inhibiting factor against aggregation

A calorimetric study at 298 K
  • Marcella Niccoli
  • Rosario Oliva
  • Giuseppina Castronuovo
Article
First Online:
Received:
Accepted:

Abstract

With the aim of better understanding how cyclodextrins can inhibit protein aggregation, a calorimetric study is reported concerning the determination of the thermodynamic properties characterizing the interaction process between natural or modified cyclodextrins and two model proteins: lysozyme and ovalbumin. The study will examine how the interaction depends on the dimensions of cyclodextrins, on the nature of their chemical modifications, and on the conformational state of the proteins. To that, the interaction has been studied in buffer, where proteins are in their native form, and in 8 mol kg−1 urea where they are in the denatured form. The technique employed is the isothermal calorimetry, which allows, in the case of the formation of a complex, to obtain the complete thermodynamic framework of the association process: enthalpy, association constant, Gibbs energy and entropy. The values and signs of these quantities will allow to investigate the forces acting in the interaction. The dimensions of the cavity and the presence of modifications on the cyclodextrin play a major role, determining the forces acting in the complexation process. The two proteins, in their native form, do not form complexes with natural cyclodextrins. Alkylated cyclodextrins, instead, form complexes with both proteins. In 8 mol kg−1 urea, where proteins are denatured, lysozyme binds to the α- and β-cyclodextrins examined, while ovalbumin forms complexes only with substituted β-cyclodextrins. The enthalpy–entropy compensation underlines that the association processes are determined by the changes experienced by water in the hydration shells of the interacting substances.

Keywords

Cyclodextrins Lysozyme Ovalbumin Microcalorimetry Aggregation 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8:E501–7.CrossRefGoogle Scholar
  2. 2.
    Chi EY, Krishnan S, Randolph TW, Carpenter JF. Physical stability of proteins in aqueous solution: mechanism and driving forces in nonnative protein aggregation. Pharm Res. 2003;20:1325–36.CrossRefGoogle Scholar
  3. 3.
    Cleland JL, Wang DIC. Cosolvent assisted protein refolding. Biotechnology (N Y). 1990;8:1274–8.CrossRefGoogle Scholar
  4. 4.
    Karruppiah N, Sharma A. Cyclodextrins as protein folding aids. Biochem Biophys Res Commun. 1995;211:60–6.CrossRefGoogle Scholar
  5. 5.
    Georgiou G, Valax P, Ostermeier M, Horowitz PM. Folding and aggregation of TEM 6-lactamase: analogies with the formation of inclusion bodies in Escherichia coli. Protein Sci. 1994;3:1953–60.CrossRefGoogle Scholar
  6. 6.
    Tandon S, Horowitz PM. Detergent-assisted refolding of guanidinium chloride-denatured rhodanese. The effects of the concentration and type of detergent. J Biol Chem. 1987;262:4486–91.Google Scholar
  7. 7.
    Randolph TW, Carpenter JF. Engineering challenges of protein formulations. AIChE J. 2007;53:1902–7.CrossRefGoogle Scholar
  8. 8.
    Frokjaer S, Otzen DE. Protein drug stability: a formulation challenge. Nat Rev Drug Discov. 2005;4:298–306.CrossRefGoogle Scholar
  9. 9.
    Yi Z, Qasim MA, Qasim S, Warrington TL, Laskowski M. Ring-toss: capping highly exposed tyrosyl or tryptophyl residues in proteins with β-cyclodextrin. Biochim Biophys Acta. 2006;1760:372–9.CrossRefGoogle Scholar
  10. 10.
    Otzen DE, Knudsen BR, Aachmann F, Larsen KL, Wimmer R. Structural basis for cyclodextrins’ suppression of human growth hormone aggregation. Protein Sci. 2002;11:1779–87.CrossRefGoogle Scholar
  11. 11.
    Kim SH, Zhang J, Jiang Y, Zhou HM, Yan HB. Assisting the reactivation of guanidine hydrochloride-denatured aminoacylase by hydroxypropyl cyclodextrins. Biophys J. 2006;91:686–93.CrossRefGoogle Scholar
  12. 12.
    Aachmann F, Otzen DE, Larsen KL, Wimmer R. Structural background of cyclodextrin–protein interactions. Protein Eng. 2003;16:905–12.CrossRefGoogle Scholar
  13. 13.
    Dotsikas Y, Loukas YL. Kinetic degradation study of insulin complexed with methyl-β-cyclodextrin. Confirmation of complexation with electrospray mass spectrometry and 1H NMR. J Pharmaceut Biomed. 2002;29:487–94.CrossRefGoogle Scholar
  14. 14.
    Qin XR, Abe H, Nakanishi H. NMR and CD studies on the interaction of Alzheimer β-amyloid peptide (12–28) with β-cyclodextrin. Biochem Biophys Res Commun. 2002;297:1011–5.CrossRefGoogle Scholar
  15. 15.
    Koushik KN, Bandi N, Kompella UB. Interaction of [D-Trp6, des-Gly10] LHRH ethylamide and hydroxyl-propyl-β-cyclodextrin (HPβCD): thermodynamics of interaction and protection from degradation by α-chymotrypsin. Pharm Dev Technol. 2001;6:595–606.CrossRefGoogle Scholar
  16. 16.
    Lovatt M, Cooper A, Camilleri A. Energetics of cyclodextrin-induced dissociation of insulin. Eur Biophys J. 1996;24:354–7.CrossRefGoogle Scholar
  17. 17.
    Horsky J, Pitha J. Inclusion complexes of proteins: interaction of cyclodextrins with peptides containing aromatic amino acids studied by competitive spectrophotometry. J Incl Phenom Mol. 1994;18:291–300.CrossRefGoogle Scholar
  18. 18.
    Khodarahmi R, Yazdanparast R. Refolding of chemically denatured α-amylase in dilution additive mode. Biochim Biophys Acta. 2004;1674:175–81.Google Scholar
  19. 19.
    Tavornvipas S, Hirayama F, Takeda S, Arima H, Uekama K. Effects of cyclodextrins on chemically and thermally induced unfolding and aggregation of lysozyme and basic fibroblast growth factor. J Pharm Sci. 2006;95:2722–9.CrossRefGoogle Scholar
  20. 20.
    Niccoli M, Castronuovo G. The conformational stability of ovalbumin and lysozyme in the aqueous solutions of various cosolvents. J Therm Anal Calorim. 2015;123:2149–56.CrossRefGoogle Scholar
  21. 21.
    Parmar AS, Muschol M. hydration and hydrodynamic interactions of lysozyme: effects of chaotropic versus kosmotropic ions. Biophys J. 2009;97:590–8.CrossRefGoogle Scholar
  22. 22.
    Castronuovo G, Niccoli M. The influence of cosolvents on hydrophilic and hydrophobic interactions. Calorimetric studies of parent and alkylated cyclomaltooligosaccharides in concentrated aqueous solutions of ethanol or urea. Carbohydr Res. 2008;343:2771–5.CrossRefGoogle Scholar
  23. 23.
    Eftink M, Biltonen R. Biological microcalorimetry, Beezer AE, editor, London: Academic Press; 1980.Google Scholar
  24. 24.
    Serno T, Geidobler R, Winter G. Protein stabilization by cyclodextrins in the liquid and dried state. Adv Drug Deliv Rev. 2011;63:1086–106.CrossRefGoogle Scholar
  25. 25.
    Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discov. 2004;3:1023–35.CrossRefGoogle Scholar
  26. 26.
    Yamamoto T, Fukui N, Hori A, Matsui Y. Circular dichroism and fluorescence spectroscopy studies of the effect of cyclodextrins on the thermal stability of chicken egg white lysozyme in aqueous solution. J Mol Struct. 2006;782:60–6.CrossRefGoogle Scholar
  27. 27.
    Rekharsky MV, Inoue Y. Complexation thermodynamics of cyclodextrins. Chem Rev. 1998;98:1875–917.CrossRefGoogle Scholar
  28. 28.
    Rekharsky MV, Mayhew MP, Goldberg RN, Ross PD, Yamashoji Y, Inoue Y. Thermodynamic and nuclear magnetic resonance study of the reactions of α- and β-cyclodextrin with acids, aliphatic amines, and cyclic alcohols. J Phys Chem. 1997;101:87–100.CrossRefGoogle Scholar
  29. 29.
    Liu L, Guo Q. The driving forces in the inclusion complexation of cyclodextrins. J Incl Phenom Macrocycl Chem. 2002;42:1–14.CrossRefGoogle Scholar
  30. 30.
    Castronuovo G, Niccoli M, Varriale L. Complexation forces in aqueous solutions. Calorimetric studies of the association of 2-hydroxypropyl-β-cyclodextrin with monocarboxylic acids or cycloalkanols. Tetrahedron. 2007;63:7047–52.CrossRefGoogle Scholar
  31. 31.
    Castronuovo G, Niccoli M. The cavity elongation effect. Calorimetric studies of the complexes of long-chain carboxylic acids with methyl-α-cyclodextrin in aqueous solutions. J Incl Phenom Macrocycl Chem. 2007;58:289–94.CrossRefGoogle Scholar
  32. 32.
    Cooper A. Effect of cyclodextrins on the thermal stability of globular proteins. J Am Chem Soc. 1992;114:9208–9.CrossRefGoogle Scholar
  33. 33.
    Weiss MS, Palm GJ, Hilgenfeld R. Crystallization, structure solution and refinement of hen egg-white lysozyme at pH 8.0 in the presence of MPD. Acta Crystallogr Sect D. 2000;56:952–8.CrossRefGoogle Scholar
  34. 34.
    Rekharsky MV, Inoue Y. Chiral recognition thermodynamic of β-cyclodextrin: the thermodynamic origin of enantioselectivity and the enthalpy entropy compensation effect. J Am Chem Soc. 2000;122:4418–35.CrossRefGoogle Scholar
  35. 35.
    Lumry R, Rajender S. Enthalpy–entropy compensation phenomena in water solutions of proteins and small molecules: a ubiquitous property of water. Biopolymers. 1970;9:1125–12227.CrossRefGoogle Scholar
  36. 36.
    Grunwald E, Steel C. Solvent reorganization and thermodynamic enthalpy–entropy compensation. J Am Chem Soc. 1995;117:5687–92.CrossRefGoogle Scholar
  37. 37.
    Meo L, D’Anna PF, Gruttadauria M, Riela S, Noto R. Thermodynamics of binding between α- and β-cyclodextrins and some p-nitro-aniline derivatives: reconsidering the enthalpy–entropy compensation effect. Tetrahedron. 2004;60:9099–111.CrossRefGoogle Scholar
  38. 38.
    Tabushi I, Kiyosuke Y, Sugimoto T, Yamamura K. Approach to the aspects of driving force of inclusion by α-cyclodextrin. J Am Chem Soc. 1978;100:916–9.CrossRefGoogle Scholar
  39. 39.
    Inoue Y, Hakushi T, Liu Y, Tong L, Shen B, Jin D. Thermodynamics of molecular recognition by cyclodextrins. 1. Calorimetric titration of inclusion complexation of naphthalenesulfonates with α-, β-, and γ-cyclodextrins: enthalpy–entropy compensation. J Am Chem Soc. 1993;115:475–81.CrossRefGoogle Scholar

Copyright information

© Akadémiai Kiadó, Budapest, Hungary 2016

Authors and Affiliations

  1. 1.Department of Chemical SciencesUniversity Federico II of NaplesNaplesItaly

Personalised recommendations