Written by Dr. Andrew Martin, Institute of Structural and Molecular Biology, University College London
Anna Tramontano (14 July 1957 – 10 March 2017), Professor of Biochemistry at the “Sapienza” University in Rome, was an outstanding scientist who made hugely important contributions to our understanding of antibody structure.
She obtained her PhD in physics from the University of Naples in 1980, but then moved to a post doc at the University of California, San Francisco. At a time when molecular graphics meant using specialized hardware – some the size of a small refrigerator – she developed a software package which was later commercialized as InsightII. In 1988, she moved to the European Molecular Biology Laboratory (EMBL) in Heidelberg to work with Arthur Lesk on analysis and modelling of antibodies. Between 1989 and 1990, together with Cyrus Chothia in Cambridge, Anna and Arthur published three key papers on the conformation of antibody complementarity-determining regions (CDRs) [1-3] – a development of the idea of canonical conformations of CDRs first published by Cyrus, Arthur and others in 1986 [4]. At this time, I was doing my D.Phil. in Oxford with Tony Rees on modelling antibodies and, to be frank, we didn’t believe this work! They were claiming that five of the six hypervariable antibody CDRs adopted only a small number of conformations defined by the length of the loop and the presence of a small number of key residues both within, and outside, the CDRs. However, this was based on analysis of only about eight available structures from the billions and billions of possible antibodies. Indeed, when the third of those papers came out [5], our view seemed to be reinforced – it appeared to be an exception to the rules – and we expected that there would be lots of these exceptions in future. However, with over 1000 antibody structures now available, some enhancements to the simple rules in those papers are still able to predict the conformations of five of the six CDRs with high accuracy.
In the early 1990s, Anna returned to a research institute in Rome that was then acquired by Merck & Co. She was involved in developing methods for designing both inhibitors and proteins and in protein modelling and docking. She continued to publish in the area of antibodies throughout the 1990s including work on phage display libraries [6-9], modelling [10-13], docking [14] and epitope prediction [15].
In 2001, she became a full professor at the Sapienza University in Rome where she continued her interest in protein structure, but also started to look at RNA molecules and their structure, but hardly published on antibodies again until 2008 when she developed the PIGS server for the automatic prediction of antibody structure [16, 17]. She then revived her interest in antibodies, among other things looking at the structural repertoire of immunoglobulin lambda light chains [18], the association of light and heavy variable domains [19], and mutations in paired light and heavy chains in chronic lymphocytic leukemia B cells [20]. In 2012, she created a database of antibodies together with a set of integrated tools known as DIGIT [21], a complement to servers such as IMGT, SAbDab and our own abYsis. Since then she has developed the proABC server for predicting interactions in antibody-antigen complexes [22], improved the modelling of CDR-H3 [23]; developed tools for antibody humanization [24]; developed methods for profiling antigen regions recognized by serum antibodies from NextGen sequencing [25] and methods for comparison and clustering of antibody binding sites [26].
Anna was a Fellow and Vice President of the International Society of Computational Biology (ISCB), which is responsible for the largest international bioinformatics conference (Intelligent Systems for Molecular Biology (ISMB)). She was also an organizer of the European Conference on Computational Biology (ECCB) and, with John Moult, of the Critical Assessment of Structure Prediction (CASP) experiment held every other year to assess progress on protein modelling. She was passionate about training in Bioinformatics and about encouraging young scientists.
Here I have focussed on her work on antibodies, but she was hugely influential in many areas of Bioinformatics. She will be greatly missed by the scientific community, and by me personally. She was always very supportive of my research and nominated me as an expert on the nomenclature of antibody-based drugs to the WHO-INN. Her science and the scientists that she has mentored and trained will remain as her lasting legacy.
1. Tramontano A, Chothia C, Lesk AM. Structural determinants of the conformations of medium-sized loops in proteins. Proteins. 1989;6(4):382-94. PMID: 2622909.
2. Chothia C, Lesk AM, Tramontano A, Levitt M, Smith-Gill SJ, Air G, Sheriff S, Padlan EA, Davies D, Tulip WR, et al. Conformations of immunoglobulin hypervariable regions. Nature. 1989 Dec 21-28;342(6252):877-83. PMID: 2687698.
3. Tramontano A, Chothia C, Lesk AM. Framework residue 71 is a major determinant of the position and conformation of the second hypervariable region in the VH domains of immunoglobulins. J Mol Biol. 1990 Sep 5;215(1):175-82. PMID: 2118959.
4. Chothia C, Lesk AM, Levitt M, Amit AG, Mariuzza RA, Phillips SE, Poljak RJ.The predicted structure of immunoglobulin D1.3 and its comparison with the crystal structure. Science. 1986 Aug 15;233(4765):755-8. PMID: 3090684.
5. Tramontano A, Chothia C, Lesk AM. Framework residue 71 is a major determinant of the position and conformation of the second hypervariable region in the VH domains of immunoglobulins. J Mol Biol. 1990 Sep 5;215(1):175-82. PMID: 2118959.
6. Leplae R, Tramontano A. PLANET: a phage library analysis expert tool.Physiol Chem Phys Med NMR. 1995;27(4):331-8. PMID: 8768788.
7. Cortese R, Monaci P, Nicosia A, Luzzago A, Felici F, Galfré G, Pessi A, Tramontano A, Sollazzo M. Identification of biologically active peptides using random libraries displayed on phage. Curr Opin Biotechnol. 1995 Feb;6(1):73-80. PMID: 7534506.
8. Luzzago A, Felici F, Tramontano A, Pessi A, Cortese R. Mimicking of discontinuous epitopes by phage-displayed peptides, I. Epitope mapping of human H ferritin using a phage library of constrained peptides. Gene. 1993 Jun 15;128(1):51-7. PMID: 7685301.
9. Tramontano A, Pizzi E, Felici F, Luzzago A, Nicosia A, Cortese R. A database system for handling phage library-derived sequences. Gene. 1993 Jun 15;128(1):143-4. PMID: 8508956.
10. Tramontano A, Lesk AM. Proteins. 1992 Jul;13(3):231-45. Common features of the conformations of antigen-binding loops in immunoglobulins and application to modeling loop conformations. PMID: 1603812.
11. Morea V, Tramontano A, Rustici M, Chothia C, Lesk AM. Conformations of the third hypervariable region in the VH domain of immunoglobulins. J Mol Biol. 1998 Jan 16;275(2):269-94. PMID: 9466909.
12. Morea V, Tramontano A, Rustici M, Chothia C, Lesk AM .Antibody structure, prediction and redesign. Biophys Chem. 1997 Oct;68(1-3):9-16. PMID: 9468606
13. Morea V, Lesk AM, Tramontano A. Antibody modeling: implications for engineering and design. Methods. 2000 Mar;20(3):267-79. PMID: 10694450.
14. Helmer-Citterich M, Rovida E, Luzzago A, Tramontano A. Modelling antibody-antigen interactions: ferritin as a case study. Mol Immunol. 1995 Sep;32(13):1001-10. PMID: 7476997.
15. Pizzi E, Cortese R, Tramontano A. Mapping epitopes on protein surfaces. Biopolymers. 1995 Nov;36(5):675-80. PMID: 7578958.
16. Marcatili P1, Rosi A, Tramontano A. PIGS: automatic prediction of antibody structures. Bioinformatics. 2008 Sep 1;24(17):1953-4. doi: 10.1093/bioinformatics/btn341. PMID: 18641403.
17. Lepore R, Olimpieri PP, Messih MA, Tramontano A. PIGSPro: prediction of immunoGlobulin structures v2. Nucleic Acids Res. 2017 May 4. doi: 10.1093/nar/gkx334. PMID: 28472367.
18. Chailyan A, Marcatili P, Cirillo D, Tramontano A. Structural repertoire of immunoglobulin λ light chains. Proteins. 2011 May;79(5):1513-24. doi: 10.1002/prot.22979. PMID: 21365679.
19. Chailyan A, Marcatili P, Tramontano A. The association of heavy and light chain variable domains in antibodies: implications for antigen specificity. FEBS J. 2011 Aug;278(16):2858-66. doi: 10.1111/j.1742-4658.2011.08207.x. PMID: 21651726.
20. Ghiotto F, Marcatili P, Tenca C, Calevo MG, Yan XJ, Albesiano E, Bagnara D, Colombo M, Cutrona G, Chu CC, Morabito F, Bruno S, Ferrarini M, Tramontano A, Fais F, Chiorazzi N. Mutation pattern of paired immunoglobulin heavy and light variable domains in chronic lymphocytic leukemia B cells. Mol Med. 2011;17(11-12):1188-95. doi: 10.2119/molmed.2011.00104. PMID: 21785810.
21. Chailyan A, Tramontano A, Marcatili P. A database of immunoglobulins with integrated tools: DIGIT. Nucleic Acids Res. 2012 Jan;40(Database issue):D1230-4. doi: 10.1093/nar/gkr806. PMID: 22080506.
22. Olimpieri PP, Chailyan A, Tramontano A, Marcatili P. Prediction of site-specific interactions in antibody-antigen complexes: the proABC method and server. Bioinformatics. 2013 Sep 15;29(18):2285-91. doi: 10.1093/bioinformatics/btt369. PMID: 23803466.
23. Messih MA, Lepore R, Marcatili P, Tramontano A. Improving the accuracy of the structure prediction of the third hypervariable loop of the heavy chains of antibodies. Bioinformatics. 2014 Oct;30(19):2733-40. doi: 10.1093/bioinformatics/btu194. PMID: 24930144
24. Olimpieri PP, Marcatili P, Tramontano A. Tabhu: tools for antibody humanization. Bioinformatics. 2015 Feb 1;31(3):434-5. doi: 10.1093/bioinformatics/btu667. PMID: 25304777.
25. Domina M, Lanza Cariccio V, Benfatto S, D’Aliberti D, Venza M, Borgogni E, Castellino F, Biondo C, D’Andrea D, Grassi L, Tramontano A, Teti G, Felici F, Beninati C. Rapid profiling of the antigen regions recognized by serum antibodies using massively parallel sequencing of antigen-specific libraries. PLoS One. 2014 Dec 4;9(12):e114159. doi: 10.1371/journal.pone.0114159. PMID: 25473968.
26. Di Rienzo L, Milanetti E, Lepore R, Olimpieri PP, Tramontano A. Superposition-free comparison and clustering of antibody binding sites: implications for the prediction of the nature of their antigen. Scientific Reports 2017;7:45053.
