Antibody CDR loops as ensembles in solution vs. canonical clusters from X-ray structures

References

• Leavy O. Therapeutic antibodies: past, present and future. Nat Rev Immunol. 2010;10:297–11.
   PubMed Web of Science ®Google Scholar
• Reichert JM. Antibodies to watch in 2017. mAbs. 2016;9:167–81.
   PubMed Web of Science ®Google Scholar
• Kaplon H, Reichert JM. Antibodies to watch in 2019. mAbs. 2019;11:219–38.
   PubMed Web of Science ®Google Scholar
• Carter PJ. Introduction to current and future protein therapeutics: A protein engineering perspective. Exp Cell Res. 2011;317:1261–69.
   PubMed Web of Science ®Google Scholar
• Chothia C, Lesk AM. Canonical structures for the hypervariable regions of immunoglobulins. J Mol Biol. 1987;196:901–17.
   PubMed Web of Science ®Google Scholar
• 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;342:877–83.
   PubMed Web of Science ®Google Scholar
• Bassing CH, Swat W, Alt FW. The mechanism and regulation of chromosomal V(D)J recombination. Cell. 2002;109:S45–55.
   PubMed Web of Science ®Google Scholar
• Market E, Papavasiliou FN. V(D)J recombination and the evolution of the adaptive immune system. PLoS Biol. 2003;1:e16.
   PubMed Web of Science ®Google Scholar
• Townsend CL, Laffy JMJ, Wu Y-CB, Silva O’Hare J, Martin V, Kipling D, Fraternali F, Dunn-Walters DK. Significant differences in physicochemical properties of human immunoglobulin Kappa and Lambda CDR3 regions. Front Immunol. 2016;7:388–388.
   PubMed Web of Science ®Google Scholar
• Martin ACR, Thornton JM. Structural families in loops of homologous proteins: automatic classification, modelling and application to antibodies. J Mol Biol. 1996;263:800–15.
   PubMed Web of Science ®Google Scholar
• Dunbar J, Krawczyk K, Leem J, Baker T, Fuchs A, Georges G, Shi J, Deane CM. SAbDab: the structural antibody database. Nucleic Acids Res. 2013;42:D1140–6.
   PubMed Web of Science ®Google Scholar
• Dunbar J, Krawczyk K, Leem J, Marks C, Nowak J, Regep C, Georges G, Kelm S, Popovic B, Deane CM. SAbPred: a structure-based antibody prediction server. Nucleic Acids Res. 2016;44:W474–8.
   PubMed Web of Science ®Google Scholar
• Adolf-Bryfogle J, Xu Q, North B, Lehmann A, Dunbrack RL. PyIgClassify: a database of antibody CDR structural classifications. Nucleic Acids Res. 2015;43:D432–8.
   PubMed Web of Science ®Google Scholar
• Marcatili P, Rosi A, Tramontano A. PIGS: automatic prediction of antibody structures. Bioinformatics. 2008;24:1953–54.
   PubMed Web of Science ®Google Scholar
• Weitzner BD, Jeliazkov JR, Lyskov S, Marze N, Kuroda D, Frick R, Adolf-Bryfogle J, Biswas N, Dunbrack RL Jr, Gray JJ. Modeling and docking of antibody structures with Rosetta. Nat Protoc. 2017;12:401.
   PubMed Web of Science ®Google Scholar
• Kuroda D, Shirai H, Jacobson MP, Nakamura H. Computer-aided antibody design. Protein Eng Des Sel. 2012;25:507–22.
   PubMed Web of Science ®Google Scholar
• Al-Lazikani B, Lesk AM, Chothia C. Standard conformations for the canonical structures of immunoglobulins1. J Mol Biol. 1997;273:927–48.
   PubMed Web of Science ®Google Scholar
• Lefranc M-P, Giudicelli V, Ginestoux C, Jabado-Michaloud J, Folch G, Bellahcene F, Wu Y, Gemrot E, Brochet X, Lane J, et al. IMGT®, the international ImMunoGeneTics information system®. Nucleic Acids Res. 2008;37:D1006–12.
   PubMed Web of Science ®Google Scholar
• Kabat EA. National Institutes of Health (U.S.), Columbia University. Sequences of proteins of immunological interest. Bethesda (MD): U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health; 1991.
   Google Scholar
• North B, Lehmann A, Dunbrack RL Jr. A new clustering of antibody CDR loop conformations. J Mol Biol. 2011;406:228–56.
   PubMed Web of Science ®Google Scholar
• Fernández-Quintero ML, Math BF, Loeffler JR, Liedl KR. Transitions of CDR-L3 loop canonical cluster conformations on the micro-to-millisecond timescale. Front Immunol. 2019;10:2652.
   PubMed Web of Science ®Google Scholar
• Fernández-Quintero ML, Kraml J, Georges G, Liedl KR. CDR-H3 loop ensemble in solution – conformational selection upon antibody binding. mAbs. 2019;11(6):1077-1088.
   PubMed Web of Science ®Google Scholar
• Hülsmeyer M, Chames P, Hillig RC, Stanfield RL, Held G, Coulie PG, Alings C, Wille G, Saenger W, Uchanska-Ziegler B, et al. A major histocompatibility complex·peptide-restricted antibody and T cell receptor molecules recognize their target by distinct binding modes: CRYSTAL STRUCTURE OF HUMAN LEUKOCYTE ANTIGEN (HLA)-A1·MAGE-A1 IN COMPLEX WITH FAB-HYB3. J Biol Chem. 2005;280:2972–80.
   PubMed Web of Science ®Google Scholar
• Yin J, Mundorff EC, Yang PL, Wendt KU, Hanway D, Stevens RC, Schultz PG. A comparative analysis of the immunological evolution of antibody 28B4. Biochemistry. 2001;40:10764–73.
   PubMed Web of Science ®Google Scholar
• Morstadt L, Bohm A, Yüksel D, Kumar K, Stollar BD, Baleja JD. Engineering and characterization of a single chain surrogate light chain variable domain. Protein Sci. 2008;17:458–65.
   PubMed Web of Science ®Google Scholar
• Shiroishi M, Yokota A, Tsumoto K, Kondo H, Nishimiya Y, Horii K, Matsushima M, Ogasahara K, Yutani K, Kumagai I. Structural evidence for entropic contribution of salt bridge formation to a protein antigen-antibody interaction: THE CASE OF HEN LYSOZYME-HyHEL-10 Fv COMPLEX. J Biol Chem. 2001;276:23042–50.
   PubMed Web of Science ®Google Scholar
• Spinelli S, Frenken L, Bourgeois D, Ron LD, Bos W, Verrips T, Anguille C, Cambillau C, Tegonil M. The crystal structure of a llama heavy chain variable domain. Nat Struct Biol. 1996;3:752–57.
   PubMedGoogle Scholar
• Reid C, Rushe M, Jarpe M, van Vlijmen H, Dolinski B, Qian F, Cachero TG, Cuervo H, Yanachkova M, Nwankwo C, et al. Structure activity relationships of monocyte chemoattractant proteins in complex with a blocking antibody. Protein Eng Des Sel. 2006;19:317–24.
   PubMed Web of Science ®Google Scholar
• Almog O, Benhar I, Vasmatzis G, Tordova M, Lee B, Pastan I, Gilliland GL. Crystal structure of the disulfide-stabilized Fv fragment of anticancer antibody B1: conformational influence of an engineered disulfide bond. Proteins Struct Funct Bioinforma. 1998;31:128–38.
   PubMed Web of Science ®Google Scholar
• Fernández-Quintero ML, Loeffler JR, Kraml J, Kahler U, Kamenik AS, Liedl KR. Characterizing the diversity of the CDR-H3 loop conformational ensembles in relationship to antibody binding properties. Front Immunol. 2019;9:3065.
   PubMed Web of Science ®Google Scholar
• Regep C, Georges G, Shi J, Popovic B, Deane CM. The H3 loop of antibodies shows unique structural characteristics. Proteins Struct Funct Bioinforma. 2017;85:1311–18.
   PubMed Web of Science ®Google Scholar
• Patten PA, Gray NS, Yang PL, Marks CB, Wedemayer GJ, Boniface JJ, Stevens RC, Schultz PG. The immunological evolution of catalysis. Science. 1996;271:1086–91.
   PubMed Web of Science ®Google Scholar
• Zhang H, Liu JH, Yang W, Springer T, Shimaoka M, Wang JH. Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1. Proc Natl Acad Sci. 2009;106:18345–50.
   PubMed Web of Science ®Google Scholar
• Eigenbrot C, Gonzalez T, Mayeda J, Carter P, Werther W, Hotaling T, Fox J, Kessler J. X-ray structures of fragments from binding and nonbinding versions of a humanized anti-CD18 antibody: structural indications of the key role of VH residues 59 to 65. Proteins Struct Funct Bioinforma. 1994;18:49–62.
   PubMed Web of Science ®Google Scholar
• Teplyakov A, Obmolova G, Malia TJ, Luo J, Muzammil S, Sweet R, Almagro JC, Gilliland GL. Structural diversity in a human antibody germline library. mAbs. 2016;8:1045–63.
   PubMed Web of Science ®Google Scholar
• Pauling L. A theory of the structure and process of formation of antibodies*. J Am Chem Soc. 1940;62:2643–57.
   Google Scholar
• Foote J, Milstein C. Conformational isomerism and the diversity of antibodies. Proc Natl Acad Sci U S A. 1994;91:10370–74.
   PubMed Web of Science ®Google Scholar
• Morea V, Lesk AM, Tramontano A. Antibody modeling: implications for engineering and design. Methods. 2000;20:267–79.
   PubMed Web of Science ®Google Scholar
• James LC, Tawfik DS. Conformational diversity and protein evolution – a 60-year-old hypothesis revisited. Trends Biochem Sci. 2003;28:361–68.
   PubMed Web of Science ®Google Scholar
• Teplyakov A, Gilliland GL. Canonical structures of short CDR-L3 in antibodies. Proteins. 2014;82:1668–73.
   PubMed Web of Science ®Google Scholar
• Nowak J, Baker T, Georges G, Kelm S, Klostermann S, Shi J, Sridharan S, Deane CM. Length-independent structural similarities enrich the antibody CDR canonical class model. mAbs. 2016;8:751–60.
   PubMed Web of Science ®Google Scholar
• Rapp CS, Pollack RM. Crystal packing effects on protein loops. Proteins Struct Funct Bioinforma. 2005;60:103–09.
   PubMed Web of Science ®Google Scholar
• Luo J, Obmolova G, Huang A, Strake B, Teplyakov A, Malia T, Muzammil S, Zhao Y, Gilliland GL, Feng Y. Coevolution of antibody stability and Vκ CDR-L3 canonical structure. J Mol Biol. 2010;402:708–19.
   PubMed Web of Science ®Google Scholar
• Marks C, Deane CM. Antibody H3 structure prediction. Comput Struct Biotechnol J. 2017;15:222–31.
   PubMed Web of Science ®Google Scholar
• Labute P. Protonate3D: assignment of ionization states and hydrogen coordinates to macromolecular structures. Proteins. 2009;75:187–205.
   PubMed Web of Science ®Google Scholar
• Molecular Operating Environment (MOE). 1010 Sherbrooke St. West, Suite #910. Montreal (QC, Canada,H3A 2R7): Cambridge Computational Group (CCG); 2018.
   Google Scholar
• Case DA, Betz RM, Cerutti DS, Cheatham TE III, Darden TA, Duke RE, Giese TJ, Gohlke H, Goetz AW, Homeyer N, et al. AMBER 2016. San Francisco: University of California; 2016.
   Google Scholar
• Roe DR, Cheatham TE. PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Comput. 2013;9:3084–95.
   PubMed Web of Science ®Google Scholar
• Hub JS, de Groot BL, Grubmüller H, Groenhof G. Quantifying artifacts in Ewald simulations of inhomogeneous systems with a net charge. J Chem Theory Comput. 2014;10:381–90.
   PubMed Web of Science ®Google Scholar
• Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983;79:926–35.
   Web of Science ®Google Scholar
• Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE, Simmerling C. ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J Chem Theory Comput. 2015;11:3696–713.
   PubMed Web of Science ®Google Scholar
• Wallnoefer HG, Liedl KR, Fox T. A challenging system: free energy prediction for factor Xa. J Comput Chem. 2011;32:1743–52.
   PubMed Web of Science ®Google Scholar
• Barducci A, Bussi G, Parrinello M. Well-tempered metadynamics: a smoothly converging and tunable free-energy method. Phys Rev Lett. 2008;100:020603.
   PubMed Web of Science ®Google Scholar
• Biswas M, Lickert B, Stock G. Metadynamics enhanced markov modeling of protein dynamics. J Phys Chem B. 2018;122:5508–14.
   PubMed Web of Science ®Google Scholar
• Barducci A, Bonomi M, Parrinello M. Metadynamics. Wiley Interdiscip Rev Comput Mol Sci. 2011;1:826–43.
   Web of Science ®Google Scholar
• Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1–2:19–25.
   Google Scholar
• Pronk S, Páll S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, Shirts MR, Smith JC, Kasson PM, van der Spoel D, et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics. 2013;29:845–54.
   PubMed Web of Science ®Google Scholar
• Tribello GA, Bonomi M, Branduardi D, Camilloni C, Bussi G. PLUMED 2: new feathers for an old bird. Comput Phys Commun. 2014;185:604–13.
   Web of Science ®Google Scholar
• James LC, Tawfik DS. Structure and kinetics of a transient antibody binding intermediate reveal a kinetic discrimination mechanism in antigen recognition. Proc Natl Acad Sci U S A. 2005;102:12730.
   PubMed Web of Science ®Google Scholar
• Shao J, Tanner SW, Thompson N, Cheatham TE. Clustering molecular dynamics trajectories: 1. characterizing the performance of different clustering algorithms. J Chem Theory Comput. 2007;3:2312–34.
   PubMed Web of Science ®Google Scholar
• Salomon-Ferrer R, Götz AW, Poole D, Le Grand S, Walker RC. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit solvent particle Mesh Ewald. J Chem Theory Comput. 2013;9:3878–88.
   PubMed Web of Science ®Google Scholar
• Miyamoto S, Kollman PA. Settle: an analytical version of the SHAKE and RATTLE algorithm for rigid water models. J Comput Chem. 1992;13:952–62.
   Web of Science ®Google Scholar
• Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR. Molecular dynamics with coupling to an external bath. J Chem Phys. 1984;81:3684–90.
   Web of Science ®Google Scholar
• Adelman SA, Doll JD. Generalized Langevin equation approach for atom/solid‐surface scattering: general formulation for classical scattering off harmonic solids. J Chem Phys. 1976;64:2375–88.
   Web of Science ®Google Scholar
• Scherer MK, Trendelkamp-Schroer B, Paul F, Pérez-Hernández G, Hoffmann M, Plattner N, Wehmeyer C, Prinz J-H, Noé F. PyEMMA 2: a software package for estimation, validation, and analysis of markov models. J Chem Theory Comput. 2015;11:5525–42.
   PubMed Web of Science ®Google Scholar
• Chodera JD, Noé F. Markov state models of biomolecular conformational dynamics. Curr Opin Struct Biol. 2014;25:135–44.
   PubMed Web of Science ®Google Scholar
• Likas A, Vlassis NJ, Verbeek J. The global k-means clustering algorithm. Biometrics. 2003;36:451–61.
   Google Scholar
• Röblitz S, Weber M. Fuzzy spectral clustering by PCCA+: application to Markov state models and data classification. Adv Data Anal Classif. 2013;7:147–79.
   Web of Science ®Google Scholar
• Karush J. On the Chapman-Kolmogorov Equation. Ann Math Stat. 1961;32:1333–37.
   Google Scholar
• Miroshin RN. Special solutions of the Chapman–Kolmogorov equation for multidimensional-state Markov processes with continuous time. Vestn St Petersburg Univ Math. 2016;49:122–29.
   Web of Science ®Google Scholar
• Wu H, Noé F. Variational approach for learning Markov processes from time series data. J Nonlinear Sci. 2017;30:23–66.
   Google Scholar