Skip to main content
SpringerLink
Log in

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

  • Original Paper
  • Published:
European Biophysics Journal Aims and scope Submit manuscript

Abstract

In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the head-group, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC). Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the head-group. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phase-transition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Atkinson J, Epand RF, Epand RM (2008) Tocopherols and tocotrienols in membranes. A critical review. Free Radic Biol Med 44:739–764

    Article  PubMed  CAS  Google Scholar 

  • Berendsen HJC, Postma JPM, van Gunsteren WF, Dinola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690

    Article  CAS  Google Scholar 

  • BioByte Corp., 201 West 4th St., Suite 204, Claremont, CA 91711, United States

  • Cegelski L, Rice CV, O' Connor RD, Caruano AL, Tochtrop GR, Cai ZY, Covey DF, Schaefer J (2006) Mapping the locations of estradiol and potent neuroprotective analogues in phospholipid bilayers by REDOR. Drug Dev Res 66:93–102

    Article  Google Scholar 

  • Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8592

    Article  CAS  Google Scholar 

  • Fabris S, Federico M, Giampietro R, Stevanato R (2008) Antioxidant properties of resveratrol and piceid on lipid peroxidation in micelles and monolamellar liposomes. Biophys Chem 125:76–83

    Article  Google Scholar 

  • Fotakis C, Gega S, Siapi E, Potamitis C, Viras K, Moutevelis-Minakakis P, Kokotos G, Durdagi S, Grdadolnik S, Sartori B, Rappolt M, Mavromoustakos T (2010) Drug interactions at the bilayer interface and receptor site induced by the novel synthetic pyrrolidinone analog MMK3. Biochim Biophys Acta 1798:422–432

    Article  PubMed  CAS  Google Scholar 

  • Guo J, Yang D, Chari R, Tian X, Pavlopoulos S, Lu D, Makriyannis A (2008) Magnetically aligned bicelles to study the orientation of lipophilic ligands in membrane bilayers. J Med Chem 41:6793–6799

    Article  Google Scholar 

  • Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18:1463–1472

    Article  CAS  Google Scholar 

  • Houslay MD, Stanley KK (1982) Dynamics of biological membranes. Wiley, New York

    Google Scholar 

  • Kandt C, Ash WL, Tieleman DP (2007) Setting up and running molecular dynamics simulations of membrane proteins. Methods 41:475–488

    Article  PubMed  CAS  Google Scholar 

  • Koynova R, Caffrey M (1998) Phases and phase transitions of the phosphatidylcholines. Biophys Biochim Acta 1376:91–145 (and reference therein)

    CAS  Google Scholar 

  • Kyrikou I, Hadjikakou SK, Kovala-Demertzi D, Viras K, Mavromoustakos T (2004a) Effects of non-steroid anti-inflammatory drugs in membrane bilayers. Chem Phys Lipids 132:157–169

    Article  PubMed  CAS  Google Scholar 

  • Kyrikou I, Daliani I, Mavromoustakos T, Maswadeh H, Demetzos C, Hatziantoniou S, Giatrellis S, Nounesis G (2004b) The modulation of thermal properties of vinblastine by cholesterol in membrane bilayers. Biochim Biophys Acta 1661:1–8

    Article  PubMed  CAS  Google Scholar 

  • Leo A, Hoekman D (2000) Calculating log P(oct) with no missing fragments; the problem of estimating new interaction parameters. Perspect Drug Discov Design 18:19–38

    Article  CAS  Google Scholar 

  • Lindhal E, Hess B, van der Spoel D (2001) GROMACS 3.0: a package for molecular simulation and trajectory analysis. J Mol Model 7:306–317

    Google Scholar 

  • Martel P, Makriyannis A, Mavromoustakos T, Kelly K, Jeffrey KR (1993) Topography of tetrahydrocannabinol in model membranes using neutron diffraction. Biochim Biophys Acta 1151:51–58

    Article  PubMed  CAS  Google Scholar 

  • Mavromoustakos T, Daliani I (1999) Effects of cannabinoids in membrane bilayers containing cholesterol. Biochim Biophys Acta 1420:252–265

    Article  PubMed  CAS  Google Scholar 

  • Mavromoustakos T, Theodoropoulou E (1998) A combined use of 13C-cross polarization/magic angle spinning, 13C-magic angle spinning and 31P-nuclear magnetic spectroscopy with Differential Scanning Calorimetry to study cannabinoid-membrane interactions. Chem Phys Lipids 92:37–52

    Article  CAS  Google Scholar 

  • Mavromoustakos T, Yang DP, Broderick W, Fournier D, Herbette LG, Makriyannis (1991) A small angle X-Ray diffraction studies on the topography of cannabinoids in synaptic plasma membranes. Pharmacol Biochem 40:547–552

    Article  CAS  Google Scholar 

  • Mavromoustakos T, Yang D, Makriyannis A (1994) Topography of Alphaxalone and ∆16-alphaxalone in membrane bilayers containing cholesterol. Biochim Biophys Acta 1194:69–74

    Article  PubMed  CAS  Google Scholar 

  • Mavromoustakos T, Yang DP, Makriyannis A (1995a) Small angle x-ray diffraction and differential scanning calorimetric studies on O-methyl-(-)-∆8-Tetrahydrocannabinol and its 5′ iodinated derivative in membrane bilayers Biochim. Biophys Acta-Biomembranes 1237:183–188

    Article  Google Scholar 

  • Mavromoustakos T, Yang DP, Makriyannis A (1995b) Effects of the anesthetic steroids alphaxalone and its inactive analog ∆16 -analog on the thermotropic properties of membrane bilayers. A model for membrane perturbation. Biochim Biophys Acta 1239:257–264

    Article  PubMed  Google Scholar 

  • Mavromoustakos T, De-Ping Yang, Makriyannis A (1996a) Topography and thermotropic properties of cannabinoids in brain sphingomyelin bilayers. Life Sci 59:1969–1979

    Article  PubMed  CAS  Google Scholar 

  • Mavromoustakos T, Theodoropoulou E, Papahatjis D, Kourouli T, De-Ping Yang, Trumbore M, Makriyannis A (1996b) Studies on the thermotropic effects of cannabinoids on phosphatidylcholine bilayers using differential scanning calorimetry and small angle X-ray diffraction. Biochim Biophys Acta 1281:235–244

    Article  PubMed  Google Scholar 

  • Mavromoustakos T, Theodoropoulou E, Yang DP (1997) The use of high-resolution solid-state NMR spectroscopy and differential scanning calorimetry to study interactions of anaesthetic steroids with membrane. Biochim Biophys Acta 1328:65–73

    Article  PubMed  CAS  Google Scholar 

  • Mavromoustakos T, Papahatjis D, Laggner P (2001) Differential membrane fluidization by active and inactive cannabinoid analogs. Biochim Biophys Acta 1512:183–190

    Article  PubMed  CAS  Google Scholar 

  • Parrinello M, Rahman A (1981) Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys 52:182–190

    Article  Google Scholar 

  • Patra M, Karttunen M, Hyvönen M, Falck E, Lindqvist P, Vattulainen I (2003) Molecular dynamics simulations of lipid bilayers: major artifacts due to truncating electrostatic interactions. Biophys J 84:3636–3645

    Article  PubMed  CAS  Google Scholar 

  • Patra M, Karttunen M, Hyvönen M, Falck E, Vattulainen P (2004) Lipid bilayers driven to a wrong lane in molecular dynamics simulations by subtle changes in long-range electrostatic interactions. J Phys Chem B 108:4485–4494

    Article  CAS  Google Scholar 

  • Privat C, Telo JP, Bernardes-Genisson V, Vieira A, Souchard JP, Nepveu F (2002) Antioxidant properties of trans-E-Viniferin as compared to stilbene derivatives in aqueous and nonaqueous media. J Agric Food Chem 50:1213–1217

    Article  PubMed  CAS  Google Scholar 

  • Sarpietro MG, Spatafora C, Tringali C, Micieli D, Castelli F (2007) Interaction of resveratrol and its trimethyl and triacetyl derivatives with biomembrane models studied by differential scanning calorimetry. J Agric Food Chem 55:3720–3728

    Article  PubMed  CAS  Google Scholar 

  • Simpkins JW, Yi KD, Yang SH, Dykens JA (2010) Mitochondrial mechanisms of estrogen neuroprotection. Biophys Acta 1800:1113–1120

    CAS  Google Scholar 

  • Skretas G, Meligova A, Villalonga-Barber C, Mitsiou DJ, Alexis MN, Micha-Screttas M, Steele BR, Screttas CG, Wood DW (2007) Engineered chimeric enzymes as tools for drug discovery: generating reliable bacterial screens for the detection, discovery, and assessment of estrogen receptor modulators. J Am Chem Soc 129:8443–8457

    Article  PubMed  CAS  Google Scholar 

  • Van Gunsteren WF, Billeter SR, Eising AA, Hunenberger PH, Kruger P, Mark AE, Scott WRP, Tironi IG (1996) Biomolecular simulation: the GROMOS96 manual and user guide.Vdf Hochschulverlag

  • Villalonga-Barber C, Meligova AK, Alexi X, Steele BR, Kouzinos CE, Screttas CG, Katsanou ES, Micha-Screttas M, Alexis MN (2011) New hydroxystilbenoid derivatives endowed with neuroprotective activity and devoid of interference with estrogen and aryl hydrocarbon receptor-mediated transcription. Bioorg Med Chem 19:339–351

    Google Scholar 

  • Wesolowska O, Kuzdzal M, Strancar J, Michalak K (2009) Interaction of the chemopreventive agent resveratrol and its metabolite, piceatannol, with model membranes. Biochim Biophys Acta 1788:1851–1860

    Article  PubMed  CAS  Google Scholar 

  • Yang DP, Mavromoustakos T, Beshah K, Makriyannis A (1992) Amphipathic interactions of cannabinoids with membranes. A comparison between ∆8-THC and its O-methyl analog using differential scanning calorimetry, X-ray diffraction and solid state 2H-NMR. Biochim Biophys Acta 1103:25–36

    Article  PubMed  CAS  Google Scholar 

  • Yang DP, Mavromoustakos T, Makriyannis A (1993) Small angle X-ray diffraction studies of ∆8-tetrahydrocannabinol and its O-methyl analog in membranes. Life Sci 53:117–122

    Article  Google Scholar 

  • Zoumpoulakis P, Daliani I, Zervou M, Kyrikou I, Siapi E, Lamprinidis G, Mikros E, Mavromoustakos T (2003) Losartan’s molecular basis of interaction with membranes and AT1 receptor. Chem Phys Lipids 125:13–25

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the EU Marie Curie Host Fellowship for Early Stage Research Training (EST) Programme MEST-CT-2005-020575 and a Center of Excellence Research program from the General Secretariat for Research and Technology. C. Koukoulitsa is a recipient of a Hrakleitos II scholarship.

Author information

Authors and Affiliations

  1. Chemistry Department, University of Athens, Zographou, 15784, Athens, Greece

    Catherine Koukoulitsa & Thomas Mavromoustakos

  2. Institute for Biocomplexity and Informatics, Department of Biological Sciences, University of Calgary, Calgary, AB, Canada

    Serdar Durdagi

  3. Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Vas. Constantinou 48, 11635, Athens, Greece

    Eleni Siapi, Carolina Villalonga-Barber, Barry R. Steele, Maria Micha-Screttas & Thomas Mavromoustakos

  4. Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Vas. Constantinou 48, 11635, Athens, Greece

    Xanthippi Alexi & Michael N. Alexis

  5. School of Pharmacy, University of Athens, Zographou, 15784, Athens, Greece

    Anna Tsantili-Kakoulidou

Authors
  1. Catherine Koukoulitsa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Serdar Durdagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eleni Siapi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carolina Villalonga-Barber
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xanthippi Alexi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Barry R. Steele
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maria Micha-Screttas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael N. Alexis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna Tsantili-Kakoulidou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thomas Mavromoustakos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Mavromoustakos.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koukoulitsa, C., Durdagi, S., Siapi, E. et al. Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity. Eur Biophys J 40, 865–875 (2011). https://doi.org/10.1007/s00249-011-0705-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00249-011-0705-4

Keywords

Search

Navigation