Structurally Mapping Antibody Repertoires

Every human possesses millions of distinct antibodies. It is now possible to analyze this diversity via next-generation sequencing of immunoglobulin genes (Ig-seq). This technique produces large volume sequence snapshots of B-cell receptors that are indicative of the antibody repertoire. In this paper, we enrich these large-scale sequence datasets with structural information. Enriching a sequence with its structural data allows better approximation of many vital features, such as its binding site and specificity. Here, we describe the structural annotation of antibodies pipeline that maps the outputs of large Ig-seq experiments to known antibody structures. We demonstrate the viability of our protocol on five separate Ig-seq datasets covering ca. 35 m unique amino acid sequences from ca. 600 individuals. Despite the great theoretical diversity of antibodies, we find that the majority of sequences coming from such studies can be reliably mapped to an existing structure.

[1]  G. Oster,et al.  Theoretical studies of clonal selection: minimal antibody repertoire size and reliability of self-non-self discrimination. , 1979, Journal of theoretical biology.

[2]  J. Davies,et al.  Molecular Biology of the Cell , 1983, Bristol Medico-Chirurgical Journal.

[3]  S. Tonegawa.  Somatic generation of antibody diversity , 1983, Nature.

[4]  A. Lesk,et al.  Canonical structures for the hypervariable regions of immunoglobulins. , 1987, Journal of molecular biology.

[5]  A. Lesk,et al.  Conformations of immunoglobulin hypervariable regions , 1989, Nature.

[6]  C. J. Oss.  Hydrophobic, hydrophilic and other interactions in epitope-paratope binding. , 1995 .

[7]  C. V. van Oss.  Hydrophobic, hydrophilic and other interactions in epitope-paratope binding. , 1995, Molecular immunology.

[8]  L. Fanning,et al.  Development of the immunoglobulin repertoire. , 1996, Clinical immunology and immunopathology.

[9]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[10]  C. Deane,et al.  CODA: A combined algorithm for predicting the structurally variable regions of protein models , 2001, Protein science : a publication of the Protein Society.

[11]  N. Sinha,et al.  Differences in electrostatic properties at antibody-antigen binding sites: implications for specificity and cross-reactivity. , 2002, Biophysical journal.

[12]  Andrew C. R. Martin,et al.  Analysis of the antigen combining site: correlations between length and sequence composition of the hypervariable loops and the nature of the antigen. , 2003, Journal of molecular biology.

[13]  J. Skolnick,et al.  TM-align: a protein structure alignment algorithm based on the TM-score , 2005, Nucleic acids research.

[14]  Michael Conrad,et al.  Antibody-antigen recognition: A canonical structure paradigm , 1996, Journal of Molecular Evolution.

[15]  Bruce Tidor,et al.  Computational design of antibody-affinity improvement beyond in vivo maturation , 2007, Nature Biotechnology.

[16]  Leonard G Presta,et al.  Molecular engineering and design of therapeutic antibodies. , 2008, Current opinion in immunology.

[17]  M. Egholm,et al.  Measurement and Clinical Monitoring of Human Lymphocyte Clonality by Massively Parallel V-D-J Pyrosequencing , 2009, Science Translational Medicine.

[18]  Jan Berka,et al.  Precise determination of the diversity of a combinatorial antibody library gives insight into the human immunoglobulin repertoire , 2009, Proceedings of the National Academy of Sciences.

[19]  Yoonjoo Choi,et al.  FREAD revisited: Accurate loop structure prediction using a database search algorithm , 2010, Proteins.

[20]  Philip E. Bourne,et al.  IEDB-3D: structural data within the immune epitope database , 2010, Nucleic Acids Res..

[21]  Stephen L. Hauser,et al.  Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation , 2011, Proceedings of the National Academy of Sciences.

[22]  C. Nusbaum,et al.  High-Resolution Description of Antibody Heavy-Chain Repertoires in Humans , 2011, PloS one.

[23]  Philip E. Bourne,et al.  Immune epitope database analysis resource , 2012, Nucleic Acids Res..

[24]  Simon J. Henderson,et al.  Monoclonal antibody therapeutics: history and future. , 2012, Current opinion in pharmacology.

[25]  Current and experimental antibody-based therapeutics: insights, breakthroughs, setbacks and future directions. , 2012 .

[26]  Scott D Boyd,et al.  Convergent antibody signatures in human dengue. , 2013, Cell host & microbe.

[27]  G. Ippolito,et al.  Intrinsic bias and public rearrangements in the human immunoglobulin Vλ light chain repertoire , 2013, Genes and Immunity.

[28]  A. Yang,et al.  Origins of specificity and affinity in antibody–protein interactions , 2014, Proceedings of the National Academy of Sciences.

[29]  Joseph Kaplinsky,et al.  Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells , 2014, Proceedings of the National Academy of Sciences.

[30]  S. Quake,et al.  The promise and challenge of high-throughput sequencing of the antibody repertoire , 2014, Nature Biotechnology.

[31]  Juan C Almagro,et al.  Second antibody modeling assessment (AMA‐II) , 2014, Proteins.

[32]  Jiye Shi,et al.  SAbDab: the structural antibody database , 2013, Nucleic Acids Res..

[33]  George Georgiou,et al.  In-depth determination and analysis of the human paired heavy- and light-chain antibody repertoire , 2014, Nature Medicine.

[34]  Johannes Trück,et al.  BCR repertoire sequencing: different patterns of B cell activation after two Meningococcal vaccines , 2015, Immunology and cell biology.

[35]  Johannes Trück,et al.  Analysis of B Cell Repertoire Dynamics Following Hepatitis B Vaccination in Humans, and Enrichment of Vaccine-specific Antibody Sequences , 2015, EBioMedicine.

[36]  Johannes Trück,et al.  In-Depth Assessment of Within-Individual and Inter-Individual Variation in the B Cell Receptor Repertoire , 2015, Front. Immunol..

[37]  Johannes Trück,et al.  Identification of Antigen-Specific B Cell Receptor Sequences Using Public Repertoire Analysis , 2015, The Journal of Immunology.

[38]  Johannes Trück,et al.  B-cell repertoire dynamics after sequential hepatitis B vaccination and evidence for cross-reactive B-cell activation , 2016, Genome Medicine.

[39]  Jiye Shi,et al.  ABodyBuilder: Automated antibody structure prediction with data–driven accuracy estimation , 2016, mAbs.

[40]  J. Galson,et al.  Investigating the effect of AS03 adjuvant on the plasma cell repertoire following pH1N1 influenza vaccination , 2016, Scientific Reports.

[41]  Anna Fowler,et al.  The Diversity and Molecular Evolution of B-Cell Receptors during Infection , 2016, Molecular biology and evolution.

[42]  Charlotte M. Deane,et al.  ANARCI: antigen receptor numbering and receptor classification , 2015, Bioinform..

[43]  C. Deane,et al.  Length-independent structural similarities enrich the antibody CDR canonical class model , 2016, mAbs.

[44]  Jeffrey J. Gray,et al.  Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires , 2016, Proceedings of the National Academy of Sciences.

[45]  Cédric R. Weber,et al.  Learning the High-Dimensional Immunogenomic Features That Predict Public and Private Antibody Repertoires , 2017, The Journal of Immunology.

[46]  C. Deane,et al.  How B-Cell Receptor Repertoire Sequencing Can Be Enriched with Structural Antibody Data , 2017, Front. Immunol..

[47]  Alicia P. Higueruelo,et al.  Arpeggio: A Web Server for Calculating and Visualising Interatomic Interactions in Protein Structures , 2017, Journal of molecular biology.