The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

Science Translational Medicine

Volumn 10, Issue 448, 2018, Pages

  Havenar Daughton, Colin ^a,b   Sarkar, Anita ^b   Kulp, Daniel W ^b,c   Toy, Laura ^a,b   Hu, Xiaozhen ^b   Deresa, Isaiah ^a   Kalyuzhniy, Oleksandr ^b   Kaushik, Kirti ^a,b   Upadhyay, Amit A ^d   Menis, Sergey ^b   Landais, Elise ^b   Cao, Liwei ^b   Diedrich, Jolene K ^b   Kumar, Sonu ^b   Schiffner, Torben ^b   Reiss, Samantha M ^a,b   Seumois, Grégory ^a   Yates, John R ^b   Paulson, James C ^b   Bosinger, Steven E ^d   Wilson, Ian A ^b   Schief, William R ^b,e   Crotty, Shane ^a,b,f   more..

^a LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY   (United States)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

^c WISTAR INSTITUTE   (United States)

^d EMORY UNIVERSITY   (United States)

^e MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^f UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EOD GT8; HUMAN IMMUNODEFICIENCY VIRUS VACCINE; N6 ANTIBODY; NEUTRALIZING ANTIBODY; PCIN63 ANTIBODY; UNCLASSIFIED DRUG; VRC01 ANTIBODY; VRC23 ANTIBODY; ANTIBODY; CD4 ANTIGEN; EPITOPE;

ANTIBODY AFFINITY; ANTIBODY COMBINING SITE; ANTIBODY RESPONSE; ARTICLE; B LYMPHOCYTE; CELL STRUCTURE; CONTROLLED STUDY; EX VIVO STUDY; GERMLINE MUTATION; HUMAN; HUMAN CELL; IMMUNE RESPONSE; IMMUNIZATION; PRIORITY JOURNAL; SEQUENCE ANALYSIS; AMINO ACID SEQUENCE; BINDING SITE; CHEMISTRY; DONOR; HUMAN IMMUNODEFICIENCY VIRUS 1; IMMUNOLOGY;

AIDS VACCINES; AMINO ACID SEQUENCE; ANTIBODIES; ANTIBODIES, NEUTRALIZING; B-LYMPHOCYTES; BINDING SITES; CD4 ANTIGENS; EPITOPES, B-LYMPHOCYTE; HIV-1; HUMANS; TISSUE DONORS;

EID: 85049384377     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aat0381     Document Type: Article

References (57)

1. D. J. Mandell, E. A. Coutsias, T. Kortemme, Sub-angstrom accuracy in protein loop reconstruction by robotics-inspired conformational sampling. Nat. Methods 6, 551-552 (2009).
2. S. A. Plotkin, Correlates of protection induced by vaccination. Clin. Vaccine Immunol. 17, 1055-1065 (2010).
3. W. C. Koff, D. R. Burton, P. R. Johnson, B. D. Walker, C. R. King, G. J. Nabel, R. Ahmed, M. K. Bhan, S. A. Plotkin, Accelerating next-generation vaccine development for global disease prevention. Science 340, 1232910 (2013).
4. D. R. Burton, What are the most powerful immunogen design vaccine strategies? Reverse vaccinology 2.0 shows great promise. Cold Spring Harb. Perspect. Biol. 9, a030262 (2017).
5. P. D. Kwong, What are the most powerful immunogen design vaccine strategies? A structural biologist's perspective. Cold Spring Harb. Perspect. Biol. 9, a029470 (2017).
6. R. Rappuoli, M. J. Bottomley, U. D'Oro, O. Finco, E. De Gregorio, Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design. J. Exp. Med. 213, 469-481 (2016).
7. J. G. Jardine, T. Ota, D. Sok, M. Pauthner, D. W. Kulp, O. Kalyuzhniy, P. D. Skog, T. C. Thinnes, D. Bhullar, B. Briney, S. Menis, M. Jones, M. Kubitz, S. Spencer, Y. Adachi, D. R. Burton, W. R. Schief, D. Nemazee, Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen. Science 349, 156-161 (2015).
8. J. Jardine, J.-P. Julien, S. Menis, T. Ota, O. Kalyuzhniy, A. McGuire, D. Sok, P.-S. Huang, S. MacPherson, M. Jones, T. Nieusma, J. Mathison, D. Baker, A. B. Ward, D. R. Burton, L. Stamatatos, D. Nemazee, I. A. Wilson, W. R. Schief, Rational HIV immunogen design to target specific germline B cell receptors. Science 340, 711-716 (2013).
9. J. M. Steichen, D. W. Kulp, T. Tokatlian, A. Escolano, P. Dosenovic, R. L. Stanfield, L. E. McCoy, G. Ozorowski, X. Hu, O. Kalyuzhniy, B. Briney, T. Schiffner, F. Garces, N. T. Freund, A. D. Gitlin, S. Menis, E. Georgeson, M. Kubitz, Y. Adachi, M. Jones, A. A. Mutafyan, D. S. Yun, C. T. Mayer, A. B. Ward, D. R. Burton, I. A. Wilson, D. J. Irvine, M. C. Nussenzweig, W. R. Schief, HIV vaccine design to target germline precursors of glycan-dependent broadly neutralizing antibodies. Immunity 45, 483-496 (2016).
10. L. Stamatatos, M. Pancera, A. T. McGuire, Germline-targeting immunogens. Immunol. Rev. 275, 203-216 (2017).
11. A. Escolano, J. M. Steichen, P. Dosenovic, D. W. Kulp, J. Golijanin, D. Sok, N. T. Freund, A. D. Gitlin, T. Oliveira, T. Araki, S. Lowe, S. T. Chen, J. Heinemann, K.-H. Yao, E. Georgeson, K. L. Saye-Francisco, A. Gazumyan, Y. Adachi, M. Kubitz, D. R. Burton, W. R. Schief, M. C. Nussenzweig, Sequential immunization elicits broadly neutralizing anti-HIV-1 antibodies in Ig knockin mice. Cell 166, 1445-1458.e12 (2016).
12. B. Briney, D. Sok, J. G. Jardine, D. W. Kulp, P. Skog, S. Menis, R. Jacak, O. Kalyuzhniy, N. de Val, F. Sesterhenn, K. M. Le, A. Ramos, M. Jones, K. L. Saye-Francisco, T. R. Blane, S. Spencer, E. Georgeson, X. Hu, G. Ozorowski, Y. Adachi, M. Kubitz, A. Sarkar, I. A. Wilson, A. B. Ward, D. Nemazee, D. R. Burton, W. R. Schief, Tailored immunogens direct affinity maturation toward HIV neutralizing antibodies. Cell 166, 1459-1470.e11 (2016).
13. R. K. Abbott, J. H. Lee, S. Menis, P. Skog, M. Rossi, T. Ota, D. W. Kulp, D. Bhullar, O. Kalyuzhniy, C. Havenar-Daughton, W. R. Schief, D. Nemazee, S. Crotty, Precursor frequency and affinity determine B cell competitive fitness in germinal centers, tested with germline-targeting HIV vaccine immunogens. Immunity 48, 133-146.e6 (2018).
14. D. Sok, B. Briney, J. G. Jardine, D. W. Kulp, S. Menis, M. Pauthner, A. Wood, E.-C. Lee, K. M. Le, M. Jones, A. Ramos, O. Kalyuzhniy, Y. Adachi, M. Kubitz, S. MacPherson, A. Bradley, G. A. Friedrich, W. R. Schief, D. R. Burton, Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice. Science 353, 1557-1560 (2016).
15. C. Havenar-Daughton, J. H. Lee, S. Crotty, Tfh cells and HIV bnAbs, an immunodominance model of the HIV neutralizing antibody generation problem. Immunol. Rev. 275, 49-61 (2017).
16. D. R. Burton, L. Hangartner, Broadly neutralizing antibodies to HIV and their role in vaccine design. Annu. Rev. Immunol. 34, 635-659 (2016).
17. J. G. Jardine, D. W. Kulp, C. Havenar-Daughton, A. Sarkar, B. Briney, D. Sok, F. Sesterhenn, J. Ereño-Orbea, O. Kalyuzhniy, I. Deresa, X. Hu, S. Spencer, M. Jones, E. Georgeson, Y. Adachi, M. Kubitz, A. C. deCamp, J.-P. Julien, I. A. Wilson, D. R. Burton, S. Crotty, W. R. Schief, HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Science 351, 1458-1463 (2016).
18. P. Dosenovic, L. von Boehmer, A. Escolano, J. Jardine, N. T. Freund, A. D. Gitlin, A. T. McGuire, D. W. Kulp, T. Oliveira, L. Scharf, J. Pietzsch, M. D. Gray, A. Cupo, M. J. van Gils, K.-H. Yao, C. Liu, A. Gazumyan, M. S. Seaman, P. J. Björkman, R. W. Sanders, J. P. Moore, L. Stamatatos, W. R. Schief, M. C. Nussenzweig, Immunization for HIV-1 broadly neutralizing antibodies in human Ig knockin mice. Cell 161, 1505-1515 (2015).
19. H. B. Gristick, L. von Boehmer, A. P. West Jr., M. Schamber, A. Gazumyan, J. Golijanin, M. S. Seaman, G. Fätkenheuer, F. Klein, M. C. Nussenzweig, P. J. Bjorkman, Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site. Nat. Struct. Mol. Biol. 23, 906-915 (2016).
20. B. J. DeKosky, T. Kojima, A. Rodin, W. Charab, G. C. Ippolito, A. D. Ellington, G. Georgiou, In-depth determination and analysis of the human paired heavy- and light-chain antibody repertoire. Nat. Med. 21, 86-91 (2015).
21. A. P. West Jr., R. Diskin, M. C. Nussenzweig, P. J. Bjorkman, Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120. Proc. Natl. Acad. Sci. U.S.A. 109, E2083-E2090 (2012).
22. T. Zhou, J. Zhu, X. Wu, S. Moquin, B. Zhang, P. Acharya, I. S. Georgiev, H. R. Altae-Tran, G.-Y. Chuang, M. G. Joyce, Y. D. Kwon, N. S. Longo, M. K. Louder, T. Luongo, K. McKee, C. A. Schramm, J. Skinner, Y. Yang, Z. Yang, Z. Zhang, A. Zheng, M. Bonsignori, B. F. Haynes, J. F. Scheid, M. C. Nussenzweig, M. Simek, D. R. Burton, W. C. Koff; NISC Comparative Sequencing Program, J. C. Mullikin, M. Connors, L. Shapiro, G. J. Nabel, J. R. Mascola, P. D. Kwong, Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies. Immunity 39, 245-258 (2013).
23. J. Huang, B. H. Kang, E. Ishida, T. Zhou, T. Griesman, Z. Sheng, F. Wu, N. A. Doria-Rose, B. Zhang, S. O'Dell, G.-Y. Chuang, A. Druz, I. S. Georgiev, C. A. Schramm, A. Zheng, M. G. Joyce, M. Asokan, A. Ransier, S. Darko, S. A. Migueles, R. T. Bailer, M. K. Louder, S. M. Alam, R. Parks, G. Kelsoe, T. Von Holle, B. F. Haynes, D. C. Douek, V. Hirsch, M. S. Seaman, L. Shapiro, J. R. Mascola, P. D. Kwong, M. Connors, Identification of a CD4-binding-site antibody to HIV that evolved near-pan neutralization breadth. Immunity 45, 1108-1121 (2016).
24. T. Zhou, I. Georgiev, X. Wu, Z.-Y. Yang, K. Dai, A. Finzi, Y. D. Kwon, J. F. Scheid, W. Shi, L. Xu, Y. Yang, J. Zhu, M. C. Nussenzweig, J. Sodroski, L. Shapiro, G. J. Nabel, J. R. Mascola, P. D. Kwong, Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329, 811-817 (2010).
25. J. G. Jardine, D. Sok, J.-P. Julien, B. Briney, A. Sarkar, C.-H. Liang, E. A. Scherer, C. J. Henry Dunand, Y. Adachi, D. Diwanji, J. Hsueh, M. Jones, O. Kalyuzhniy, M. Kubitz, S. Spencer, M. Pauthner, K. L. Saye-Francisco, F. Sesterhenn, P. C. Wilson, D. M. Galloway, R. L. Stanfield, I. A. Wilson, D. R. Burton, W. R. Schief, Minimally mutated HIV-1 broadly neutralizing antibodies to guide reductionist vaccine design. PLOS Pathog. 12, e1005815 (2016).
26. I. S. Georgiev, N. A. Doria-Rose, T. Zhou, Y. D. Kwon, R. P. Staupe, S. Moquin, G.-Y. Chuang, M. K. Louder, S. D. Schmidt, H. R. Altae-Tran, R. T. Bailer, K. McKee, M. Nason, S. O'Dell, G. Ofek, M. Pancera, S. Srivatsan, L. Shapiro, M. Connors, S. A. Migueles, L. Morris, Y. Nishimura, M. A. Martin, J. R. Mascola, P. D. Kwong, Delineating antibody recognition in polyclonal sera from patterns of HIV-1 isolate neutralization. Science 340, 751-756 (2013).
27. E. Landais, Broadly neutralizing antibodies to HIV-1: Lessons from protocol C studies, paper presented at the HIV Vaccine Keystone Symposia, Steamboat Springs, CO, 26 to 30 March 2017.
28. R. Diskin, J. F. Scheid, P. M. Marcovecchio, A. P. West Jr., F. Klein, H. Gao, P. N. P. Gnanapragasam, A. Abadir, M. S. Seaman, M. C. Nussenzweig, P. J. Bjorkman, Increasing the potency and breadth of an HIV antibody by using structure-based rational design. Science 334, 1289-1293 (2011).
29. C. Yacoob, M. Pancera, V. Vigdorovich, B. G. Oliver, J. A. Glenn, J. Feng, D. N. Sather, A. T. McGuire, L. Stamatatos, Differences in allelic frequency and CDRH3 region limit the engagement of HIV Env immunogens by putative VRC01 neutralizing antibody precursors. Cell Rep. 17, 1560-1570 (2016).
30. K. J. L. Jackson, Y. Wang, B. A. Gaeta, W. Pomat, P. Siba, J. Rimmer, W. A. Sewell, A. M. Collins, Divergent human populations show extensive shared IGK rearrangements in peripheral blood B cells. Immunogenetics 64, 3-14 (2012).
31. K. H. Hoi, G. C. Ippolito, Intrinsic bias and public rearrangements in the human immunoglobulin V light chain repertoire. Genes Immun. 14, 271-276 (2013).
32. G. Arentz, L. A. Thurgood, R. Lindop, T. K. Chataway, T. P. Gordon, Secreted human Ro52 autoantibody proteomes express a restricted set of public clonotypes. J. Autoimmun. 39, 466-470 (2012).
33. T. Zhou, R. M. Lynch, L. Chen, P. Acharya, X. Wu, N. A. Doria-Rose, M. G. Joyce, D. Lingwood, C. Soto, R. T. Bailer, M. J. Ernandes, R. Kong, N. S. Longo, M. K. Louder, K. McKee, S. O'Dell, S. D. Schmidt, L. Tran, Z. Yang, A. Druz, T. S. Luongo, S. Moquin, S. Srivatsan, Y. Yang, B. Zhang, A. Zheng, M. Pancera, T. Kirys, I. S. Georgiev, T. Gindin, H.-P. Peng, A.-S. Yang; NISC Comparative Sequencing Program, J. C. Mullikin, M. D. Gray, L. Stamatatos, D. R. Burton, W. C. Koff, M. S. Cohen, B. F. Haynes, J. P. Casazza, M. Connors, D. Corti, A. Lanzavecchia, Q. J. Sattentau, R. A. Weiss, A. P. West Jr., P. J. Bjorkman, J. F. Scheid, M. C. Nussenzweig, L. Shapiro, J. R. Mascola, P. D. Kwong, Structural repertoire of HIV-1-neutralizing antibodies targeting the CD4 supersite in 14 donors. Cell 161, 1280-1292 (2015).
34. A. Bräuninger, T. Goossens, K. Rajewsky, R. Küppers, Regulation of immunoglobulin light chain gene rearrangements during early B cell development in the human. Eur. J. Immunol. 31, 3631-3637 (2001).
35. X. Wu, Z. Zhang, C. A. Schramm, M. G. Joyce, Y. Do Kwon, T. Zhou, Z. Sheng, B. Zhang, S. O'Dell, K. McKee, I. S. Georgiev, G.-Y. Chuang, N. S. Longo, R. M. Lynch, K. O. Saunders, C. Soto, S. Srivatsan, Y. Yang, R. T. Bailer, M. K. Louder; NISC Comparative Sequencing Program, B. Benjamin, R. Blakesley, G. Bouffard, S. Brooks, H. Coleman, M. Dekhtyar, M. Gregory, X. Guan, J. Gupta, J. Han, A. Hargrove, S.I. Ho, R. Legaspi, Q. Maduro, C. Masiello, B. Maskeri, J. McDowell, C. Montemayor, M. Park, N. Riebow, K. Schandler, B. Schmidt, C. Sison, M. Stantripop, J. Thomas, P. Thomas, M. Vemulapalli, A. Young, J. C. Mullikin, M. Connors, P. D. Kwong, J. R. Mascola, L. Shapiro, Maturation and diversity of the VRC01-antibody lineage over 15 years of chronic HIV-1 infection. Cell 161, 470-485 (2015).
36. G. D. Victora, M. C. Nussenzweig, Germinal centers. Annu. Rev. Immunol. 30, 429-457 (2012).
37. S. Crotty, T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529-542 (2014).
38. C. T. Mayer, A. Gazumyan, E. E. Kara, A. D. Gitlin, J. Golijanin, C. Viant, J. Pai, T. Y. Oliveira, Q. Wang, A. Escolano, M. Medina-Ramirez, R. W. Sanders, M. C. Nussenzweig, The microanatomic segregation of selection by apoptosis in the germinal center. Science 358, eaao2602 (2017).
39. X. Xiao, W. Chen, Y. Feng, Z. Zhu, P. Prabakaran, Y. Wang, M.-Y. Zhang, N. S. Longo, D. S. Dimitrov, Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogens. Biochem. Biophys. Res. Commun. 390, 404-409 (2009).
40. A. T. McGuire, A. M. Dreyer, S. Carbonetti, A. Lippy, J. Glenn, J. F. Scheid, H. Mouquet, L. Stamatatos, Antigen modification regulates competition of broad and narrow neutralizing HIV antibodies. Science 346, 1380-1383 (2014).
41. D. Angeletti, J. S. Gibbs, M. Angel, I. Kosik, H. D. Hickman, G. M. Frank, S. R. Das, A. K. Wheatley, M. Prabhakaran, D. J. Leggat, A. B. McDermott, J. W. Yewdell, Defining B cell immunodominance to viruses. Nat. Immunol. 18, 456-463 (2017).
42. Z. Otwinowski, W. Minor, Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326 (1997).
43. A. J. McCoy, R. W. Grosse-Kunstleve, P. D. Adams, M. D. Winn, L. C. Storoni, R. J. Read, Phaser crystallographic software. J. Appl. Crystallogr. 40, 658-674 (2007).
44. P. D. Adams, P. V. Afonine, G. Bunkóczi, V. B. Chen, I. W. Davis, N. Echols, J. J. Headd, L.-W. Hung, G. J. Kapral, R. W. Grosse-Kunstleve, A. J. McCoy, N. W. Moriarty, R. Oeffner, R. J. Read, D. C. Richardson, J. S. Richardson, T. C. Terwilliger, P. H. Zwart, PHENIX: A comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213-221 (2010).
45. P. Emsley, K. Cowtan, Coot: Model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126-2132 (2004).
46. V. B. Chen, W. B. Arendall III, J. J. Headd, D. A. Keedy, R. M. Immormino, G. J. Kapral, L. W. Murray, J. S. Richardson, D. C. Richardson, MolProbity: All-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12-21 (2010).
47. J. W. Labonte, J. Adolf-Bryfogle, W. R. Schief, J. J. Gray, Residue-centric modeling and design of saccharide and glycoconjugate structures. J. Comput. Chem. 38, 276-287 (2017).
48. T. Tiller, E. Meffre, S. Yurasov, M. Tsuiji, M. C. Nussenzweig, H. Wardemann, Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 329, 112-124 (2008).
49. X. Brochet, M.-P. Lefranc, V. Giudicelli, IMGT/V-QUEST: The highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucleic Acids Res. 36, W503-W508 (2008).
50. G. E. Crooks, G. Hon, J.-M. Chandonia, S. E. Brenner, WebLogo: A sequence logo generator. Genome Res. 14, 1188-1190 (2004).
51. I. Engel, G. Seumois, L. Chavez, D. Samaniego-Castruita, B. White, A. Chawla, D. Mock, P. Vijayanand, M. Kronenberg, Innate-like functions of natural killer T cell subsets result from highly divergent gene programs. Nat. Immunol. 17, 728-739 (2016).
52. A. A. Upadhyay, R. C. Kauffman, A. N. Wolabaugh, A. Cho, N. B. Patel, S. M. Reiss, C. Havenar-Daughton, R. A. Dawoud, G. K. Tharp, I. Sanz, B. Pulendran, S. Crotty, F. E.-H. Lee, J. Wrammert, S. E. Bosinger, BALDR: A computational pipeline for paired heavy and light chain immunoglobulin reconstruction in single-cell RNA-seq data. Genome Med. 10, 20 (2018).
53. L. Cao, J. K. Diedrich, D. W. Kulp, M. Pauthner, L. He, S.-K. R. Park, D. Sok, C. Y. Su, C. M. Delahunty, S. Menis, R. Andrabi, J. Guenaga, E. Georgeson, M. Kubitz, Y. Adachi, D. R. Burton, W. R. Schief, J. R. Yates III, J. C. Paulson, Global site-specific N-glycosylation analysis of HIV envelope glycoprotein. Nat. Commun. 8, 14954 (2017).
54. C. L. Gatlin, J. K. Eng, S. T. Cross, J. C. Detter, J. R. Yates, Automated identification of amino acid sequence variations in proteins by HPLC/microspray tandem mass spectrometry. Anal. Chem. 72, 757-763 (2000).
55. J. He, M. Boegli, I. Bruzas, W. Lum, L. Sagle, Patterned plasmonic nanoparticle arrays for microfluidic and multiplexed biological assays. Anal. Chem. 87, 11407-11414 (2015).
56. S. K. Park, J. D. Venable, T. Xu, J. R. Yates III, A quantitative analysis software tool for mass spectrometry-based proteomics. Nat. Methods 5, 319-322 (2008).
57. A. Leaver-Fay, M. Tyka, S. M. Lewis, O. F. Lange, J. Thompson, R. Jacak, K. W. Kaufman, P. D. Renfrew, C. A. Smith, W. Sheffler, I. W. Davis, S. Cooper, A. Treuille, D. J. Mandell, F. Richter, Y.-E. A. Ban, S. J. Fleishman, J. E. Corn, D. E. Kim, S. Lyskov, M. Berrondo, S. Mentzer, Z. Popović, J. J. Havranek, J. Karanicolas, R. Das, J. Meiler, T. Kortemme, J. J. Gray, B. Kuhlman, D. Baker, P. Bradley, Rosetta3: An object-oriented software suite for the simulation and design of macromolecules. Methods Enzymol. 487, 545-574 (2011).