Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition

被引:13
作者
Ayres, Cory M. [1 ]
Riley, Timothy P. [1 ]
Corcelli, Steven A. [1 ]
Baker, Brian M. [1 ]
机构
[1] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA
关键词
T-CELL RECOGNITION; MOLECULAR-DYNAMICS; VACCINE-DESIGN; COMPLEX; BINDING; PROTEIN; ANTIGEN; FLEXIBILITY; IMMUNOGENICITY; STABILITY;
D O I
10.1021/acs.jcim.7b00118
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In cellular immunity, T cells recognize peptide antigens bound and presented by major histocompatibility complex (MHC) proteins. The motions of peptides bound to MHC proteins play a significant role in determining immunogenicity. However, existing approaches for investigating peptide/MHC motional dynamics are challenging or of low throughput, hindering the development of algorithms for predicting immunogenicity from large databases, such as those of tumor or genetically unstable viral genomes. We addressed this by performing extensive molecular dynamics simulations on a large structural database of peptides bound to the most commonly expressed human class-I MHC protein, HLA-A*0201. The simulations reproduced experimental indicators of motion and were used to generate simple models for predicting site specific, rapid motions of bound peptides through differences in their sequence and chemical composition alone. The models can easily be applied on their own or incorporated into immunogenicity prediction algorithms. Beyond their predictive power, the models provide insight into how amino acid substitutions can influence peptide and protein motions and how dynamic information is communicated across peptides. They also indicate a link between peptide rigidity and hydrophobicity, two features known to be important in influencing cellular immune responses.
引用
收藏
页码:1990 / 1998
页数:9
相关论文
共 34 条
[1]   Signatures of mutational processes in human cancer [J].
Alexandrov, Ludmil B. ;
Nik-Zainal, Serena ;
Wedge, David C. ;
Aparicio, Samuel A. J. R. ;
Behjati, Sam ;
Biankin, Andrew V. ;
Bignell, Graham R. ;
Bolli, Niccolo ;
Borg, Ake ;
Borresen-Dale, Anne-Lise ;
Boyault, Sandrine ;
Burkhardt, Birgit ;
Butler, Adam P. ;
Caldas, Carlos ;
Davies, Helen R. ;
Desmedt, Christine ;
Eils, Roland ;
Eyfjord, Jorunn Erla ;
Foekens, John A. ;
Greaves, Mel ;
Hosoda, Fumie ;
Hutter, Barbara ;
Ilicic, Tomislav ;
Imbeaud, Sandrine ;
Imielinsk, Marcin ;
Jaeger, Natalie ;
Jones, David T. W. ;
Jones, David ;
Knappskog, Stian ;
Kool, Marcel ;
Lakhani, Sunil R. ;
Lopez-Otin, Carlos ;
Martin, Sancha ;
Munshi, Nikhil C. ;
Nakamura, Hiromi ;
Northcott, Paul A. ;
Pajic, Marina ;
Papaemmanuil, Elli ;
Paradiso, Angelo ;
Pearson, John V. ;
Puente, Xose S. ;
Raine, Keiran ;
Ramakrishna, Manasa ;
Richardson, Andrea L. ;
Richter, Julia ;
Rosenstiel, Philip ;
Schlesner, Matthias ;
Schumacher, Ton N. ;
Span, Paul N. ;
Teague, Jon W. .
NATURE, 2013, 500 (7463) :415-+
[2]   Differential utilization of binding loop flexibility in T cell receptor ligand selection and cross-reactivity [J].
Ayres, Cory M. ;
Scott, Daniel R. ;
Corcelli, Steven A. ;
Baker, Brian M. .
SCIENTIFIC REPORTS, 2016, 6
[3]   Conversion of a T cell antagonist into an agonist by repairing a defect in the TCR/peptide/MHC interface: Implications for TCR signaling [J].
Baker, BM ;
Gagnon, SJ ;
Biddison, WE ;
Wiley, DC .
IMMUNITY, 2000, 13 (04) :475-484
[4]   Structures of MART-126/27-35 peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition [J].
Borbulevych, Oleg Y. ;
Insaidoo, Francis K. ;
Baxter, Tiffany K. ;
Powell, Daniel J., Jr. ;
Johnson, Laura A. ;
Restifo, Nicholas P. ;
Baker, Brian M. .
JOURNAL OF MOLECULAR BIOLOGY, 2007, 372 (05) :1123-1136
[5]   Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: Implications for vaccine design [J].
Borbulevych, OY ;
Baxter, TK ;
Yu, ZY ;
Restifo, NP ;
Baker, BM .
JOURNAL OF IMMUNOLOGY, 2005, 174 (08) :4812-4820
[6]   Purposeful selection of variables in logistic regression [J].
Bursac, Zoran ;
Gauss, C. Heath ;
Williams, David Keith ;
Hosmer, David W. .
SOURCE CODE FOR BIOLOGY AND MEDICINE, 2008, 3 (01)
[7]   Prediction of solvent accessibility and sites of deleterious mutations from protein sequence [J].
Chen, HL ;
Zhou, HX .
NUCLEIC ACIDS RESEARCH, 2005, 33 (10) :3193-3199
[8]   Structural and functional distinctiveness of HLA-A2 allelic variants [J].
Chen, Kenneth Yuanxiang ;
Liu, Jingxian ;
Ren, Ee Chee .
IMMUNOLOGIC RESEARCH, 2012, 53 (1-3) :182-190
[9]   TCR contact residue hydrophobicity is a hallmark of immunogenic CD8+ T cell epitopes [J].
Chowell, Diego ;
Krishna, Sri ;
Becker, Pablo D. ;
Cocita, Clement ;
Shu, Jack ;
Tan, Xuefang ;
Greenberg, Philip D. ;
Klavinskis, Linda S. ;
Blattman, Joseph N. ;
Anderson, Karen S. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (14) :E1754-E1762
[10]   Modification of MHC Anchor Residues Generates Heteroclitic Peptides That Alter TCR Binding and T Cell Recognition [J].
Cole, David K. ;
Edwards, Emily S. J. ;
Wynn, Katherine K. ;
Clement, Mathew ;
Miles, John J. ;
Ladell, Kristin ;
Ekeruche, Julia ;
Gostick, Emma ;
Adams, Katherine J. ;
Skowera, Ania ;
Peakman, Mark ;
Wooldridge, Linda ;
Price, David A. ;
Sewell, Andrew K. .
JOURNAL OF IMMUNOLOGY, 2010, 185 (04) :2600-2610