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Towards the chemometric dissection of peptide – HLA-A*0201 binding affinity: comparison of local and global QSAR models


The affinities of 177 nonameric peptides binding to the HLA-A*0201 molecule were measured using a FACS-based MHC stabilisation assay and analysed using chemometrics. Their structures were described by global and local descriptors, QSAR models were derived by genetic algorithm, stepwise regression and PLS. The global molecular descriptors included molecular connectivity χ indices, κ shape indices, E-state indices, molecular properties like molecular weight and log P, and three-dimensional descriptors like polarizability, surface area and volume. The local descriptors were of two types. The first used a binary string to indicate the presence of each amino acid type at each position of the peptide. The second was also position-dependent but used five z-scales to describe the main physicochemical properties of the amino acids forming the peptides. The models were developed using a representative training set of 131 peptides and validated using an independent test set of 46 peptides. It was found that the global descriptors could not explain the variance in the training set nor predict the affinities of the test set accurately. Both types of local descriptors gave QSAR models with better explained variance and predictive ability. The results suggest that, in their interactions with the MHC molecule, the peptide acts as a complicated ensemble of multiple amino acids mutually potentiating each other.

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  1. A. Sette A. Vitiello B. Reherman P. Fowler R. Nayersina W.M. Kast C.J. Melief C. Oseroff L. Yuan J. Ruppert J. Sidney M.F. Delguercio S. Southwood R.T. Kubo R.W. Chestnut H.M. Grey F.V. Chisari (1994) J. Immunol. 153 5586 Occurrence Handle1:CAS:528:DyaK2MXis12ksbs%3D Occurrence Handle7527444

    CAS  PubMed  Google Scholar 

  2. S. Krebs D. Rognan (1998) Pharm. Acta Helv. 73 173 Occurrence Handle10.1016/S0031-6865(98)00021-1 Occurrence Handle1:CAS:528:DyaK1cXntlyqsrY%3D Occurrence Handle9861866

    Article  CAS  PubMed  Google Scholar 

  3. W.J. Pichler (2002) Toxicology 181–182 49 Occurrence Handle10.1016/S0300-483X(02)00254-8 Occurrence Handle12505284

    Article  PubMed  Google Scholar 

  4. J.P. Griffith J.L. Kim E.E. Kim M.D. Sintchak J.A. Thomson M.J. Fitzgibbon M.A. Fleming P.R. Caron K. Hsiao M.A. Navia (1995) Cell 82 507 Occurrence Handle10.1016/0092-8674(95)90439-5 Occurrence Handle1:CAS:528:DyaK2MXnsFSgtrY%3D Occurrence Handle7543369

    Article  CAS  PubMed  Google Scholar 

  5. S.G.E. Marsh J.G. Bodmer E.D. Albert W.F. Bodmer R.E. Bontrop S. Dupont H.A. Erlich J.A. Hansen B. Mach W.R. Mayr P. Parham E.W. Petersdorf T. Sasazuki G.M.T. Schreuder J.L. Strominger A. Svejgaard P.I. Terasaki (2001) Eur. J. Immunogen. 28 377 Occurrence Handle10.1046/j.1365-2370.2001.00268.x Occurrence Handle1:CAS:528:DC%2BD3MXls1Wqu7w%3D Occurrence Handle11422419

    Article  CAS  PubMed  Google Scholar 

  6. J. Bodmer (1996) Ciba Found. Symp. 197 233 Occurrence Handle1:STN:280:BymH38vpt1I%3D Occurrence Handle8827377

    CAS  PubMed  Google Scholar 

  7. G.E. Peoples P.S. Goedegebuure R. Smith D.C. Linehan I. Yoshino T.Y. Eberlein (1995) Proc. Natl. Acad. Sci. USA 92 432 Occurrence Handle1:CAS:528:DyaK2MXjt12qsbo%3D Occurrence Handle7831305

    CAS  PubMed  Google Scholar 

  8. A.J. McMichael P. Parham F.M. Brodsky J.R. Pilch (1980) J. Exp. Med. 152 IssueIDSuppl. 2 195

    Google Scholar 

  9. Y. Rongcun F. Salazar-Onfray J. Charo K.-J. Malmberg K. Evrin H. Maes C. Hising M. Petersson O. Larsson L. Lan E. Appella A. Sette E. Celis R. Kiessling (1999) J. Immunol. 163 1037 Occurrence Handle1:CAS:528:DyaK1MXksVens7g%3D Occurrence Handle10395702

    CAS  PubMed  Google Scholar 

  10. L. Rivoltini Y. Kawakami K. Sakaguchi S. Southwood A. Sette P.F. Robbins F.M. Marincola M.L. Salgaller J.R. Yannelli E. Appella S.A. Rosenberg (1995) J.␣Immunol. 154 2257 Occurrence Handle1:CAS:528:DyaK2MXjsl2qur4%3D Occurrence Handle7868898

    CAS  PubMed  Google Scholar 

  11. M.A. Saper P.J. Bjorkman D.D. Wiley (1991) J. Mol. Biol. 219 277 Occurrence Handle10.1016/0022-2836(91)90567-P Occurrence Handle1:CAS:528:DyaK3MXkvFSgtbw%3D Occurrence Handle2038058

    Article  CAS  PubMed  Google Scholar 

  12. D.R. Madden D.N. Garboczi D.C. Wiley (1993) Cell 75 693 Occurrence Handle10.1016/0092-8674(93)90490-H Occurrence Handle1:CAS:528:DyaK2cXivV2hsQ%3D%3D Occurrence Handle7694806

    Article  CAS  PubMed  Google Scholar 

  13. J. Ruppert J. Sidney E. Celis R.T. Kubo H.M. Grey A. Sette (1993) Cell 74 929 Occurrence Handle10.1016/0092-8674(93)90472-3 Occurrence Handle1:CAS:528:DyaK3sXms1yns7k%3D Occurrence Handle8104103

    Article  CAS  PubMed  Google Scholar 

  14. D.R. Madden (1995) Annu. Rev. Immunol. 13 587 Occurrence Handle1:CAS:528:DyaK2MXltFamurY%3D Occurrence Handle7612235

    CAS  PubMed  Google Scholar 

  15. I.A. Doytchinova M.J. Blythe D.R.J. Flower (2002) Proteome Res. 1 263 Occurrence Handle10.1021/pr015513z Occurrence Handle1:CAS:528:DC%2BD38Xislags7o%3D

    Article  CAS  Google Scholar 

  16. I.A. Doytchinova V.A. Walshe N.A. Jones S.E. Gloster P. Borrow D.R. Flower (2004) J. Immunol. 172 7495 Occurrence Handle1:CAS:528:DC%2BD2cXks1ahu78%3D Occurrence Handle15187128

    CAS  PubMed  Google Scholar 

  17. M. Sandberg L. Eriksson J. Jonsson M. Sjöström S. Wold (1998) J. Med. Chem. 41 2481 Occurrence Handle10.1021/jm9700575 Occurrence Handle1:CAS:528:DyaK1cXktlShuro%3D Occurrence Handle9651153

    Article  CAS  PubMed  Google Scholar 

  18. SYBYL 6.9. Tripos Inc., 1699 Hanley Road, St. Louis, MO 63144

  19. MDL QSAR 2.2. 14600 Catalina St. San Leandro CA 94577

  20. G. Stuber S. Modrow P. Hoglund L. Franksson J. Elvin H. Wolf K. Karre G. Klein (1992) Eur. J. Immunol. 22 2697 Occurrence Handle1:CAS:528:DyaK3sXlsFSj Occurrence Handle1327802

    CAS  PubMed  Google Scholar 

  21. A.R. Lopes A. Jaye L. Dorrell S. Sabally A. Alabi N.A. Jones D.R. Flower A. Groot ParticleDe P. Newton R.M. Lascar I. Williams H. Whittle A. Bertoletti P. Borrow M.K. Maini (2003) J. Immunol. 171 307 Occurrence Handle1:CAS:528:DC%2BD3sXks12jtLg%3D Occurrence Handle12817012

    CAS  PubMed  Google Scholar 

  22. Y. Chen J. Sidney S. Southwood A.L. Cox K. Sakaguchi R.A. Henderson E. Appella D.F. Hunt A. Sette V.H. Engelhard (1994) J. Immunol. 152 2874 Occurrence Handle1:CAS:528:DyaK2cXis1OltL0%3D Occurrence Handle8144888

    CAS  PubMed  Google Scholar 

  23. Daylight .Theory Manual at

  24. Hall, L.H. and Kier, L.B., In Devillers, J. (Ed.), Methods for QSAR Modeling, Gordon and Breach, London, 1999, pp

  25. Hall, L.H. and Kier, L.B., In Devillers, J. (Ed.), Topological Indices and Related Descriptors in QSAR and QSPR, Gordon and Breach, London, 1999, pp

  26. S. Hellberg M. Sjöström S. Wold (1986) Acta Chem. Scand. B40 135 Occurrence Handle1:CAS:528:DyaL2sXislyrsg%3D%3D

    CAS  Google Scholar 

  27. S. Hellberg L. Eriksson J. Jonsson F. Lindgren M. Sjöström B. Skagerberg S. Wold P. Andrews (1991) Int. J. Peptide Protein Res. 37 414 Occurrence Handle1:CAS:528:DyaK38XhsFeguw%3D%3D

    CAS  Google Scholar 

  28. R. Leardi R. Boggia M. Terrile (1992) J. Chemometrics 6 267 Occurrence Handle10.1002/cem.1180060506 Occurrence Handle1:CAS:528:DyaK3sXhs1ygurY%3D

    Article  CAS  Google Scholar 

  29. SIMCA-P 8.0. Umetrics UK Ltd., Wokingham Road, RG42 1PL, Bracknell, UK

  30. K. Falk O. Rötzschke S. Stefanovic G. Jung H.-G. Rammensee (1991) Nature, 351 290

    Google Scholar 

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Correspondence to Darren R. Flower.

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Doytchinova, I.A., Walshe, V., Borrow, P. et al. Towards the chemometric dissection of peptide – HLA-A*0201 binding affinity: comparison of local and global QSAR models. J Comput Aided Mol Des 19, 203–212 (2005).

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  • GA
  • peptides
  • PLS
  • stepwise regression
  • z-scales