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. 2000 Sep;9(9):1838–1846. doi: 10.1110/ps.9.9.1838

Structure-based prediction of binding peptides to MHC class I molecules: application to a broad range of MHC alleles.

O Schueler-Furman 1, Y Altuvia 1, A Sette 1, H Margalit 1
PMCID: PMC2144704  PMID: 11045629

Abstract

Specific binding of antigenic peptides to major histocompatibility complex (MHC) class I molecules is a prerequisite for their recognition by cytotoxic T-cells. Prediction of MHC-binding peptides must therefore be incorporated in any predictive algorithm attempting to identify immunodominant T-cell epitopes, based on the amino acid sequence of the protein antigen. Development of predictive algorithms based on experimental binding data requires experimental testing of a very large number of peptides. A complementary approach relies on the structural conservation observed in crystallographically solved peptide-MHC complexes. By this approach, the peptide structure in the MHC groove is used as a template upon which peptide candidates are threaded, and their compatibility to bind is evaluated by statistical pairwise potentials. Our original algorithm based on this approach used the pairwise potential table of Miyazawa and Jernigan (Miyazawa S, Jernigan RL, 1996, J Mol Biol 256:623-644) and succeeded to correctly identify good binders only for MHC molecules with hydrophobic binding pockets, probably because of the high emphasis of hydrophobic interactions in this table. A recently developed pairwise potential table by Betancourt and Thirumalai (Betancourt MR, Thirumalai D, 1999, Protein Sci 8:361-369) that is based on the Miyazawa and Jernigan table describes the hydrophilic interactions more appropriately. In this paper, we demonstrate how the use of this table, together with a new definition of MHC contact residues by which only residues that contribute exclusively to sequence specific binding are included, allows the development of an improved algorithm that can be applied to a wide range of MHC class I alleles.

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Selected References

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  1. Achour A., Persson K., Harris R. A., Sundbäck J., Sentman C. L., Lindqvist Y., Schneider G., Kärre K. The crystal structure of H-2Dd MHC class I complexed with the HIV-1-derived peptide P18-I10 at 2.4 A resolution: implications for T cell and NK cell recognition. Immunity. 1998 Aug;9(2):199–208. doi: 10.1016/s1074-7613(00)80602-0. [DOI] [PubMed] [Google Scholar]
  2. Altuvia Y., Schueler O., Margalit H. Ranking potential binding peptides to MHC molecules by a computational threading approach. J Mol Biol. 1995 Jun 2;249(2):244–250. doi: 10.1006/jmbi.1995.0293. [DOI] [PubMed] [Google Scholar]
  3. Altuvia Y., Sette A., Sidney J., Southwood S., Margalit H. A structure-based algorithm to predict potential binding peptides to MHC molecules with hydrophobic binding pockets. Hum Immunol. 1997 Nov;58(1):1–11. doi: 10.1016/s0198-8859(97)00210-3. [DOI] [PubMed] [Google Scholar]
  4. Balendiran G. K., Solheim J. C., Young A. C., Hansen T. H., Nathenson S. G., Sacchettini J. C. The three-dimensional structure of an H-2Ld-peptide complex explains the unique interaction of Ld with beta-2 microglobulin and peptide. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6880–6885. doi: 10.1073/pnas.94.13.6880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Betancourt M. R., Thirumalai D. Pair potentials for protein folding: choice of reference states and sensitivity of predicted native states to variations in the interaction schemes. Protein Sci. 1999 Feb;8(2):361–369. doi: 10.1110/ps.8.2.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen Y., Sidney J., Southwood S., Cox A. L., Sakaguchi K., Henderson R. A., Appella E., Hunt D. F., Sette A., Engelhard V. H. Naturally processed peptides longer than nine amino acid residues bind to the class I MHC molecule HLA-A2.1 with high affinity and in different conformations. J Immunol. 1994 Mar 15;152(6):2874–2881. [PubMed] [Google Scholar]
  7. Collins E. J., Garboczi D. N., Karpusas M. N., Wiley D. C. The three-dimensional structure of a class I major histocompatibility complex molecule missing the alpha 3 domain of the heavy chain. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1218–1221. doi: 10.1073/pnas.92.4.1218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Corr M., Boyd L. F., Padlan E. A., Margulies D. H. H-2Dd exploits a four residue peptide binding motif. J Exp Med. 1993 Dec 1;178(6):1877–1892. doi: 10.1084/jem.178.6.1877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ding Y. H., Smith K. J., Garboczi D. N., Utz U., Biddison W. E., Wiley D. C. Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids. Immunity. 1998 Apr;8(4):403–411. doi: 10.1016/s1074-7613(00)80546-4. [DOI] [PubMed] [Google Scholar]
  10. Fremont D. H., Matsumura M., Stura E. A., Peterson P. A., Wilson I. A. Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. Science. 1992 Aug 14;257(5072):919–927. doi: 10.1126/science.1323877. [DOI] [PubMed] [Google Scholar]
  11. Fremont D. H., Stura E. A., Matsumura M., Peterson P. A., Wilson I. A. Crystal structure of an H-2Kb-ovalbumin peptide complex reveals the interplay of primary and secondary anchor positions in the major histocompatibility complex binding groove. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2479–2483. doi: 10.1073/pnas.92.7.2479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gao G. F., Tormo J., Gerth U. C., Wyer J. R., McMichael A. J., Stuart D. I., Bell J. I., Jones E. Y., Jakobsen B. K. Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2. Nature. 1997 Jun 5;387(6633):630–634. doi: 10.1038/42523. [DOI] [PubMed] [Google Scholar]
  13. Garboczi D. N., Ghosh P., Utz U., Fan Q. R., Biddison W. E., Wiley D. C. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature. 1996 Nov 14;384(6605):134–141. doi: 10.1038/384134a0. [DOI] [PubMed] [Google Scholar]
  14. Garcia K. C., Degano M., Pease L. R., Huang M., Peterson P. A., Teyton L., Wilson I. A. Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science. 1998 Feb 20;279(5354):1166–1172. doi: 10.1126/science.279.5354.1166. [DOI] [PubMed] [Google Scholar]
  15. Ghendler Y., Teng M. K., Liu J. H., Witte T., Liu J., Kim K. S., Kern P., Chang H. C., Wang J. H., Reinherz E. L. Differential thymic selection outcomes stimulated by focal structural alteration in peptide/major histocompatibility complex ligands. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10061–10066. doi: 10.1073/pnas.95.17.10061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Glithero A., Tormo J., Haurum J. S., Arsequell G., Valencia G., Edwards J., Springer S., Townsend A., Pao Y. L., Wormald M. Crystal structures of two H-2Db/glycopeptide complexes suggest a molecular basis for CTL cross-reactivity. Immunity. 1999 Jan;10(1):63–74. doi: 10.1016/s1074-7613(00)80007-2. [DOI] [PubMed] [Google Scholar]
  17. Gulukota K., Sidney J., Sette A., DeLisi C. Two complementary methods for predicting peptides binding major histocompatibility complex molecules. J Mol Biol. 1997 Apr 18;267(5):1258–1267. doi: 10.1006/jmbi.1997.0937. [DOI] [PubMed] [Google Scholar]
  18. Huang E. S., Subbiah S., Levitt M. Recognizing native folds by the arrangement of hydrophobic and polar residues. J Mol Biol. 1995 Oct 6;252(5):709–720. doi: 10.1006/jmbi.1995.0529. [DOI] [PubMed] [Google Scholar]
  19. Jernigan R. L., Bahar I. Structure-derived potentials and protein simulations. Curr Opin Struct Biol. 1996 Apr;6(2):195–209. doi: 10.1016/s0959-440x(96)80075-3. [DOI] [PubMed] [Google Scholar]
  20. Jones D. T., Thornton J. M. Potential energy functions for threading. Curr Opin Struct Biol. 1996 Apr;6(2):210–216. doi: 10.1016/s0959-440x(96)80076-5. [DOI] [PubMed] [Google Scholar]
  21. Kern P. S., Teng M. K., Smolyar A., Liu J. H., Liu J., Hussey R. E., Spoerl R., Chang H. C., Reinherz E. L., Wang J. H. Structural basis of CD8 coreceptor function revealed by crystallographic analysis of a murine CD8alphaalpha ectodomain fragment in complex with H-2Kb. Immunity. 1998 Oct;9(4):519–530. doi: 10.1016/s1074-7613(00)80635-4. [DOI] [PubMed] [Google Scholar]
  22. Keskin O., Bahar I., Badretdinov A. Y., Ptitsyn O. B., Jernigan R. L. Empirical solvent-mediated potentials hold for both intra-molecular and inter-molecular inter-residue interactions. Protein Sci. 1998 Dec;7(12):2578–2586. doi: 10.1002/pro.5560071211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kondo A., Sidney J., Southwood S., del Guercio M. F., Appella E., Sakamoto H., Celis E., Grey H. M., Chesnut R. W., Kubo R. T. Prominent roles of secondary anchor residues in peptide binding to HLA-A24 human class I molecules. J Immunol. 1995 Nov 1;155(9):4307–4312. [PubMed] [Google Scholar]
  24. Kondo A., Sidney J., Southwood S., del Guercio M. F., Appella E., Sakamoto H., Grey H. M., Celis E., Chesnut R. W., Kubo R. T. Two distinct HLA-A*0101-specific submotifs illustrate alternative peptide binding modes. Immunogenetics. 1997;45(4):249–258. doi: 10.1007/s002510050200. [DOI] [PubMed] [Google Scholar]
  25. Madden D. R., Garboczi D. N., Wiley D. C. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell. 1993 Nov 19;75(4):693–708. doi: 10.1016/0092-8674(93)90490-h. [DOI] [PubMed] [Google Scholar]
  26. Madden D. R., Gorga J. C., Strominger J. L., Wiley D. C. The three-dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC. Cell. 1992 Sep 18;70(6):1035–1048. doi: 10.1016/0092-8674(92)90252-8. [DOI] [PubMed] [Google Scholar]
  27. Menssen R., Orth P., Ziegler A., Saenger W. Decamer-like conformation of a nona-peptide bound to HLA-B*3501 due to non-standard positioning of the C terminus. J Mol Biol. 1999 Jan 15;285(2):645–653. doi: 10.1006/jmbi.1998.2363. [DOI] [PubMed] [Google Scholar]
  28. Miyazawa S., Jernigan R. L. Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. J Mol Biol. 1996 Mar 1;256(3):623–644. doi: 10.1006/jmbi.1996.0114. [DOI] [PubMed] [Google Scholar]
  29. Parker K. C., Bednarek M. A., Coligan J. E. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol. 1994 Jan 1;152(1):163–175. [PubMed] [Google Scholar]
  30. Rammensee H. G., Friede T., Stevanoviíc S. MHC ligands and peptide motifs: first listing. Immunogenetics. 1995;41(4):178–228. doi: 10.1007/BF00172063. [DOI] [PubMed] [Google Scholar]
  31. Reid S. W., McAdam S., Smith K. J., Klenerman P., O'Callaghan C. A., Harlos K., Jakobsen B. K., McMichael A. J., Bell J. I., Stuart D. I. Antagonist HIV-1 Gag peptides induce structural changes in HLA B8. J Exp Med. 1996 Dec 1;184(6):2279–2286. doi: 10.1084/jem.184.6.2279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ressing M. E., Sette A., Brandt R. M., Ruppert J., Wentworth P. A., Hartman M., Oseroff C., Grey H. M., Melief C. J., Kast W. M. Human CTL epitopes encoded by human papillomavirus type 16 E6 and E7 identified through in vivo and in vitro immunogenicity studies of HLA-A*0201-binding peptides. J Immunol. 1995 Jun 1;154(11):5934–5943. [PubMed] [Google Scholar]
  33. Ruppert J., Sidney J., Celis E., Kubo R. T., Grey H. M., Sette A. Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell. 1993 Sep 10;74(5):929–937. doi: 10.1016/0092-8674(93)90472-3. [DOI] [PubMed] [Google Scholar]
  34. Schueler-Furman O., Elber R., Margalit H. Knowledge-based structure prediction of MHC class I bound peptides: a study of 23 complexes. Fold Des. 1998;3(6):549–564. doi: 10.1016/S1359-0278(98)00070-4. [DOI] [PubMed] [Google Scholar]
  35. Sette A., Buus S., Appella E., Smith J. A., Chesnut R., Miles C., Colon S. M., Grey H. M. Prediction of major histocompatibility complex binding regions of protein antigens by sequence pattern analysis. Proc Natl Acad Sci U S A. 1989 May;86(9):3296–3300. doi: 10.1073/pnas.86.9.3296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sette A., Sidney J., del Guercio M. F., Southwood S., Ruppert J., Dahlberg C., Grey H. M., Kubo R. T. Peptide binding to the most frequent HLA-A class I alleles measured by quantitative molecular binding assays. Mol Immunol. 1994 Aug;31(11):813–822. doi: 10.1016/0161-5890(94)90019-1. [DOI] [PubMed] [Google Scholar]
  37. Sette A., Vitiello A., Reherman B., Fowler P., Nayersina R., Kast W. M., Melief C. J., Oseroff C., Yuan L., Ruppert J. The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol. 1994 Dec 15;153(12):5586–5592. [PubMed] [Google Scholar]
  38. Sidney J., Grey H. M., Southwood S., Celis E., Wentworth P. A., del Guercio M. F., Kubo R. T., Chesnut R. W., Sette A. Definition of an HLA-A3-like supermotif demonstrates the overlapping peptide-binding repertoires of common HLA molecules. Hum Immunol. 1996 Feb;45(2):79–93. doi: 10.1016/0198-8859(95)00173-5. [DOI] [PubMed] [Google Scholar]
  39. Sidney J., Southwood S., del Guercio M. F., Grey H. M., Chesnut R. W., Kubo R. T., Sette A. Specificity and degeneracy in peptide binding to HLA-B7-like class I molecules. J Immunol. 1996 Oct 15;157(8):3480–3490. [PubMed] [Google Scholar]
  40. Silver M. L., Guo H. C., Strominger J. L., Wiley D. C. Atomic structure of a human MHC molecule presenting an influenza virus peptide. Nature. 1992 Nov 26;360(6402):367–369. doi: 10.1038/360367a0. [DOI] [PubMed] [Google Scholar]
  41. Skolnick J., Jaroszewski L., Kolinski A., Godzik A. Derivation and testing of pair potentials for protein folding. When is the quasichemical approximation correct? Protein Sci. 1997 Mar;6(3):676–688. doi: 10.1002/pro.5560060317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Smith K. J., Reid S. W., Harlos K., McMichael A. J., Stuart D. I., Bell J. I., Jones E. Y. Bound water structure and polymorphic amino acids act together to allow the binding of different peptides to MHC class I HLA-B53. Immunity. 1996 Mar;4(3):215–228. doi: 10.1016/s1074-7613(00)80430-6. [DOI] [PubMed] [Google Scholar]
  43. Smith K. J., Reid S. W., Stuart D. I., McMichael A. J., Jones E. Y., Bell J. I. An altered position of the alpha 2 helix of MHC class I is revealed by the crystal structure of HLA-B*3501. Immunity. 1996 Mar;4(3):203–213. doi: 10.1016/s1074-7613(00)80429-x. [DOI] [PubMed] [Google Scholar]
  44. Southwood S., Sidney J., Kondo A., del Guercio M. F., Appella E., Hoffman S., Kubo R. T., Chesnut R. W., Grey H. M., Sette A. Several common HLA-DR types share largely overlapping peptide binding repertoires. J Immunol. 1998 Apr 1;160(7):3363–3373. [PubMed] [Google Scholar]
  45. Speir J. A., Garcia K. C., Brunmark A., Degano M., Peterson P. A., Teyton L., Wilson I. A. Structural basis of 2C TCR allorecognition of H-2Ld peptide complexes. Immunity. 1998 May;8(5):553–562. doi: 10.1016/s1074-7613(00)80560-9. [DOI] [PubMed] [Google Scholar]
  46. Sturniolo T., Bono E., Ding J., Raddrizzani L., Tuereci O., Sahin U., Braxenthaler M., Gallazzi F., Protti M. P., Sinigaglia F. Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices. Nat Biotechnol. 1999 Jun;17(6):555–561. doi: 10.1038/9858. [DOI] [PubMed] [Google Scholar]
  47. Swets J. A. Measuring the accuracy of diagnostic systems. Science. 1988 Jun 3;240(4857):1285–1293. doi: 10.1126/science.3287615. [DOI] [PubMed] [Google Scholar]
  48. Thomas P. D., Dill K. A. Statistical potentials extracted from protein structures: how accurate are they? J Mol Biol. 1996 Mar 29;257(2):457–469. doi: 10.1006/jmbi.1996.0175. [DOI] [PubMed] [Google Scholar]
  49. Young A. C., Zhang W., Sacchettini J. C., Nathenson S. G. The three-dimensional structure of H-2Db at 2.4 A resolution: implications for antigen-determinant selection. Cell. 1994 Jan 14;76(1):39–50. doi: 10.1016/0092-8674(94)90171-6. [DOI] [PubMed] [Google Scholar]
  50. Zhao R., Loftus D. J., Appella E., Collins E. J. Structural evidence of T cell xeno-reactivity in the absence of molecular mimicry. J Exp Med. 1999 Jan 18;189(2):359–370. doi: 10.1084/jem.189.2.359. [DOI] [PMC free article] [PubMed] [Google Scholar]

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