HLA Moleküllerinde Peptit Ligandlarının Kompleks Stabilitesine Olan Etkisinin Araştırılması

Abstract

Hücre yüzey glikoproteinleri olan Temel Doku Uygunluk Kompleks (MHC) molekülleri yabancı antijenlere bağlanır ve onları uygun immün tanınma için antijen sunucu hücrelerin yüzeyindeki T lenfosit hücrelerine sunar. İlk olarak insanlarda lökosit hücrelerinde tanımlanmış oldukları için, aynı zamanda İnsan Lökosit Antijenleri (HLA) olarak da isimlendirilirler. Son zamanlarda peptit bazlı aşıların tasarlanması üzerine odaklanan çalışmalar, peptitin sitotoksik T hücre aracılı immün cevabı uyarma yeteneği olarak tanımlanan peptit immunojenite mekanizmasının anlaşılmasına olanak sağlamaktadır. Peptit immünojenisitesinin, peptit-HLA kompleksinin stabilitesi ile ilişkili olduğu bilinmektedir. Bu çalışmada, AIFQSSMTK and QVPLRPMTYK peptitlerine bağlanan HLA-A*03:01 ve HLA-A*11:01 alellerinin stabilitesinin temel moleküler mekanizmalarını ortaya çıkarmak için moleküler dinamik simülasyonları gerçekleştirilmiştir ve ENCOM sunucusu kullanılarak peptit rezidüleri üzerinde gerçekleştirilen tek nokta mutasyonlarının protein termostabilitesine olan tahmini etkisi araştırılmıştır. 

Keywords

• MHC Molekülü,Stabilite,Moleküler Dinamik Simülasyonu,Mutasyon,ENCOM

References

1. [1] Abbas, A. K., Lichtman, A. H., ve Pillai, S. (2015). Cellular and molecular immunology.
2. [2] Lafuente, E. M., ve Reche, P. A. (2009). Prediction of MHC-peptide binding: a systematic and comprehensive overview. Current Pharmaceutical Design, 15(28), 3209–20.
3. [3] Garrett, T. P. J., Saper, M. A., Bjorkman, P. J., Strominger, J. L., ve Wiley, D. C. (1989). Specificity pockets for the side chains of peptide antigens in HLA-Aw68 Nature, 342(6250), 692–696.
4. [4] Mamitsuka, H. (1998). Predicting peptides that bind to MHC molecules using supervised learning of hidden Markov models. Proteins, 33(4), 460–74. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9849933
5. [5] Binkowski, T. A., Marino, S. R., ve Joachimiak, A. (2012). Predicting HLA Class I Non-Permissive Amino Acid Residues Substitutions PLoS ONE, 7(8), e41710.
6. [6] Sette, A., Buus, S., Appella, E., Smith, J. A., Chesnut, R., Miles, C., Colon, S. M., ve Grey, H. M. (1989). Prediction of major histocompatibility complex binding regions of protein antigens by sequence pattern analysis. Proceedings of the National Academy of Sciences of the United States of America, 86(9), 3296–300.
7. [7] Falk, K., Rötzschke, O., Stevanovié, S., Jung, G., ve Rammensee, H.-G. (1991). Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules Nature, 351(6324), 290–296.
8. [8] Rammensee, H., Bachmann, J., Emmerich, N. P., Bachor, O. A., ve Stevanović, S. (1999). SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics, 50(3-4), 213–9.

9. [9] Zhang, G. L., Khan, A. M., Srinivasan, K. N., August, J. T., ve Brusic, V. (2005). MULTIPRED: a computational system for prediction of promiscuous HLA binding peptides Nucleic Acids Research, 33(Web Server), W172–W179.
10. [10] Zhang, G. L., Bozic, I., Kwoh, C. K., August, J. T., ve Brusic, V. (2007). Prediction of supertype-specific HLA class I binding peptides using support vector machines Journal of Immunological Methods, 320(1-2), 143–154.
11. [11] Lin, H., Ray, S., Tongchusak, S., Reinherz, E. L., ve Brusic, V. (2008). Evaluation of MHC class I peptide binding prediction servers: Applications for vaccine research BMC Immunology, 9(1), 8.
12. [12] Rognan, D., Lauemoller, S. L., Holm, A., Buus, S., ve Tschinke, V. (1999). Predicting binding affinities of protein ligands from three-dimensional models: application to peptide binding to class I major histocompatibility proteins. Journal of Medicinal Chemistry, 42(22), 4650–8.
13. [13] Tong, J. C., Tan, T. W., ve Ranganathan, S. (2004). Modeling the structure of bound peptide ligands to major histocompatibility complex. Protein Science : A Publication of the Protein Society, 13(9), 2523–32.
14. [14] Kumar, N., ve Mohanty, D. (2007). MODPROPEP: a program for knowledge-based modeling of protein-peptide complexes Nucleic Acids Research, 35(Web Server), W549–W555.
15. [15] Jojic, N., Reyes-Gomez, M., Heckerman, D., Kadie, C., ve Schueler-Furman, O. (2006). Learning MHC I--peptide binding Bioinformatics, 22(14), e227–e235.
16. [16] Sette, A., Vitiello, A., Reherman, B., Fowler, P., Nayersina, R., Kast, W. M., Melief, C. J., Oseroff, C., Yuan, L., Ruppert, J., Sidney, J., Guercio, M. F., Southwood, S., Kubo, R. T., Chesnut, R. W., Grey, H. M., ve Chisari, F.V (1994). The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. Journal of Immunology (Baltimore, Md. : 1950), 153(12), 5586–92.
17. [17] Ressing, M. E., Sette, A., Brandt, R. M., Ruppert, J., Wentworth, P. A., Hartman, M., Oseroff, C., Grey, H. M., Melief, C. J., ve Kast, W. M. (1995). 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. Journal of Immunology (Baltimore, Md. : 1950), 154(11), 5934–43.
18. [18] Harndahl, M., Rasmussen, M., Roder, G., Dalgaard Pedersen, I., Sørensen, M., Nielsen, M., ve Buus, S. (2012). Peptide-MHC class I stability is a better predictor than peptide affinity of CTL immunogenicity European Journal of Immunology, 42(6), 1405–1416.
19. [19] Lim, J. S., Kim, S., Lee, H. G., Lee, K. Y., Kwon, T. J., ve Kim, K. (1996). Selection of peptides that bind to the HLA-A2.1 molecule by molecular modelling. Molecular Immunology, 33(2), 221–30.
20. [20] Hoppes, R., Oostvogels, R., Luimstra, J. J., Wals , K., Toebes, M., Bies, L., Ekkebus, R., Rijal, P., Celie H. N., Huang, J. H., Emmelot, E., Spaapen, R. M., Lokhorst, H., Schumacher, T. N. M., Mutis, T., Rodenko, B., ve Ovaa, H. (2014). Altered Peptide Ligands Revisited: Vaccine Altered Peptide Ligands Revisited: Vaccine Design through Chemically Modified HLA-A2–Restricted T Cell Epitopes DCSupplemental.html The Journal of Immunology at Medical Library Vrije Universiteit on November The Journal of Immunology, 193(9), 4803–4813.
21. [21] Dedier, S. (2000). Thermodynamic Stability of HLA-B*2705/Peptide Complexes: Effect of Peptide and MHC Protein mutations Journal of Biological Chemistry, 275(35), 27055–27061.
22. [22] Blankenstein, T., Coulie, P. G., Gilboa, E., ve Jaffee, E. M. (2012). The determinants of tumour immunogenicity Nature Reviews Cancer, 12(4), 307–313.
23. [23] Stavrakoudis, A. (2010). Conformational flexibility in designing peptides for immunology: the molecular dynamics approach. Current Computer-Aided Drug Design, 6(3), 207–22.
24. [24] Camacho, C. J., Katsumata, Y., ve Ascherman, D. P. (2008). Structural and Thermodynamic Approach to Peptide Immunogenicity PLoS Computational Biology, 4(11), e1000231.
25. [25] Lonquety, M., Lacroix, Z., Papandreou, N., ve Chomilier, J. (2009). SPROUTS: a database for the evaluation of protein stability upon point mutation Nucleic Acids Research, 37(suppl_1), D374–D379.
26. [26] Razvi, A., ve Scholtz, J. M. (2006). Lessons in stability from thermophilic proteins Protein Science, 15(7), 1569–1578.
27. [27] Frappier, V., ve Najmanovich, R. (2015). Vibrational entropy differences between mesophile and thermophile proteins and their use in protein engineering Protein Science, 24(4), 474–483.
28. [28] Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I.N., ve Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Research, 28(1), 235–42.
29. [29] Zhang, S., Liu, J., Cheng, H., Tan, S., Qi, J., Yan, J., ve Gao, G. F. (2011). Structural basis of cross-allele presentation by HLA-A*0301 and HLA-A*1101 revealed by two HIV-derived peptide complexes Molecular Immunology, 49(1-2), 395–401.
30. [30] Li, L., ve Bouvier, M. (2004). Structures of HLA-A*1101 complexed with immunodominant nonamer and decamer HIV-1 epitopes clearly reveal the presence of a middle, secondary anchor residue. Journal of Immunology (Baltimore, Md. : 1950), 172(10), 6175–6184.
31. [31] Phillips, J. C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., Chipot, C., Skeel, R. D., Kalé, L., ve Schulten, K. (2005). Scalable molecular dynamics with NAMD Journal of Computational Chemistry, 26(16), 1781–1802.
32. [32] Brooks, B. R., Bruccoleri, R. E., Olafson, B. D., States, D. J., Swaminathan, S., ve Karplus, M. (1983). CHARMM: A program for macromolecular energy, minimization, and dynamics calculations Journal of Computational Chemistry, 4(2), 187–217.
33. [33] Eswar, N., Webb, B., Marti-Renom, M. A., Madhusudhan, M. S., Eramian, D., Shen, M., Pieper U., ve Sali, A. (2006). Comparative Protein Structure Modeling Using Modeller In Current Protocols in Bioinformatics (Vol. Chapter 5, pp. 5.6.1–5.6.30). Hoboken, NJ, USA: John Wiley & Sons, Inc.
34. [34] Frappier, V., Chartier, M., ve Najmanovich, R. J. (2015). ENCoM server: exploring protein conformational space and the effect of mutations on protein function and stability Nucleic Acids Research, 43(W1), W395–W400.
35. [35] Frappier, V., ve Najmanovich, R. (2015). Vibrational entropy differences between mesophile and thermophile proteins and their use in protein engineering Protein Science, 24(4), 474–483.
36. [36] Sidney, J., Grey, H. M., Southwood, S., Celis, E., Wentworth, P. A., del Guercio, M. F., … Sette, A. (1996). Definition of an HLA-A3-like supermotif demonstrates the overlapping peptide- binding repertoires of common HLA molecules. Human Immunology, 45(2), 79–93.
37. [37] Racape, J., Connan, F., Hoebeke, J., Choppin, J., ve Guillet, J.-G. (2006). Influence of dominant HIV-1 epitopes on HLA-A3/peptide complex formation. Proceedings of the National Academy of Sciences of the United States of America, 103(48), 18208–18213.
38. [38] Lichterfeld, M., Williams, K. L., Mui, S. K., Shah, S. S., Mothe, B. R., Sette, A., … Yu, X. G. (2006). T cell receptor cross-recognition of an HIV-1 CD8+ T cell epitope presented by closely related alleles from the HLA-A3 superfamily. International Immunology, 18(7), 1179–1188.
39. [39] Zhang, S., Liu, J., Cheng, H., Tan, S., Qi, J., Yan, J., ve Gao, G. F. (2011). Structural basis of cross-allele presentation by HLA-A*0301 and HLA-A*1101 revealed by two HIV-derived peptide complexes Molecular Immunology, 49(1–2), 395–401.
40. [40] Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, ve Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Research, 28(1), 235–42.
41. [41] Li, L., ve Bouvier, M. (2004). Structures of HLA-A*1101 complexed with immunodominant nonamer and decamer HIV-1 epitopes clearly reveal the presence of a middle, secondary anchor residue. Journal of Immunology (Baltimore, Md. : 1950), 172(10), 6175–6184.
42. [42] Phillips, J. C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., Chipot., C., Skeel, R. D., Kale ve Schulten, K. (2005). Scalable molecular dynamics with NAMD Journal of Computational Chemistry, 26(16), 1781–1802.
43. [43] Brooks, B. R., Bruccoleri, R. E., Olafson, B. D., States, D. J., Swaminathan, S., ve Karplus, M. (1983). CHARMM: A program for macromolecular energy, minimization, and dynamics calculations Journal of Computational Chemistry, 4(2), 187–217.
44. [44] Eswar, N., Webb, B., Marti-Renom, M. A., Madhusudhan, M. S., Eramian, D., Shen, M., Pieper U., ve Sali, A. (2006). Comparative Protein Structure Modeling Using Modeller In Current Protocols in Bioinformatics (Vol. Chapter 5, p. 5.6.1- 5.6.30).
45. [45] Frappier, V., Chartier, M., ve Najmanovich, R. J. (2015). ENCoM server: exploring protein conformational space and the effect of mutations on protein function and stability Nucleic Acids Research, 43(W1), W395–W400.