Espada, R.; Parra, R.G.; Mora, T.; Walczak, A.M.; Ferreiro, D.U."Inferring repeat-protein energetics from evolutionary information" (2017) PLoS Computational Biology. 13(6)
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Natural protein sequences contain a record of their history. A common constraint in a given protein family is the ability to fold to specific structures, and it has been shown possible to infer the main native ensemble by analyzing covariations in extant sequences. Still, many natural proteins that fold into the same structural topology show different stabilization energies, and these are often related to their physiological behavior. We propose a description for the energetic variation given by sequence modifications in repeat proteins, systems for which the overall problem is simplified by their inherent symmetry. We explicitly account for single amino acid and pair-wise interactions and treat higher order correlations with a single term. We show that the resulting evolutionary field can be interpreted with structural detail. We trace the variations in the energetic scores of natural proteins and relate them to their experimental characterization. The resulting energetic evolutionary field allows the prediction of the folding free energy change for several mutants, and can be used to generate synthetic sequences that are statistically indistinguishable from the natural counterparts. © 2017 Espada et al.


Documento: Artículo
Título:Inferring repeat-protein energetics from evolutionary information
Autor:Espada, R.; Parra, R.G.; Mora, T.; Walczak, A.M.; Ferreiro, D.U.
Filiación:Protein Physiology Lab, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica. Buenos Aires. / CONICET - Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina
Quantitative and Computational Biology Group, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany
Laboratoire de physique statistique, Ecole Normale Supérieure, CNRS and UPMC, Paris, 75005, France
CNRS and Laboratoire de Physique Théorique, Ecole Normale Supérieure, Paris, France
Palabras clave:ankyrin; leucine rich repeat protein; polypeptide; protein; repeat protein; tetratricopeptide repeat protein; unclassified drug; protein; amino acid sequence; Article; energy transfer; evolution; Monte Carlo method; point mutation; protein folding; protein stability; sequence alignment; statistical model; amino acid repeat; astronomy; chemical model; chemistry; energy transfer; genetics; molecular model; procedures; protein conformation; sequence analysis; structure activity relation; ultrastructure; Energy Transfer; Evolution, Chemical; Models, Chemical; Models, Molecular; Point Mutation; Protein Conformation; Protein Folding; Proteins; Repetitive Sequences, Amino Acid; Sequence Analysis, Protein; Structure-Activity Relationship
Título revista:PLoS Computational Biology
Título revista abreviado:PLoS Comput. Biol.
CAS:protein, 67254-75-5; Proteins


  • Main, E.R., Lowe, A.R., Mochrie, S.G., Jackson, S.E., Regan, L., A recurring theme in protein engineering: the design, stability and folding of repeat proteins (2005) Current opinion in structural biology, 15 (4), pp. 464-471. , 16043339
  • Sedgwick, S.G., Smerdon, S.J., The ankyrin repeat: a diversity of interactions on a common structural framework (1999) Trends in biochemical sciences, 24 (8), pp. 311-316. , 10431175
  • Kobe, B., Kajava, A.V., The leucine-rich repeat as a protein recognition motif (2001) Current opinion in structural biology, 11 (6), pp. 725-732. , 11751054
  • Blatch, G.L., Lässle, M., The tetratricopeptide repeat: a structural motif mediating protein-protein interactions (1999) Bioessays, 21 (11), pp. 932-939. , 10517866
  • Rowling, P.J., Sivertsson, E.M., Perez-Riba, A., Main, E.R., Itzhaki, L.S., Dissecting and reprogramming the folding and assembly of tandem-repeat proteins (2015) Biochemical Society Transactions, 43 (5), pp. 881-888. , 26517898
  • Brunette, T., Parmeggiani, F., Huang, P.S., Bhabha, G., Ekiert, D.C., Tsutakawa, S.E., Exploring the repeat protein universe through computational protein design (2015) Nature, , 26675729
  • Urvoas, A., Guellouz, A., Valerio-Lepiniec, M., Graille, M., Durand, D., Desravines, D.C., Design, production and molecular structure of a new family of artificial alpha-helicoidal repeat proteins (αRep) based on thermostable HEAT-like repeats (2010) Journal of molecular biology, 404 (2), pp. 307-327. , 20887736
  • Espada, R., Sánchez, I.E., Ferreiro, D.U., Detailing Protein Landscapes under Pressure (2016) Biophysical Journal, 111 (11), pp. 2339-2341. , 27926834
  • Frauenfelder, H., Function and Dynamics of Myoglobin (1987) Annals of the New York Academy of Sciences, 504, pp. 151-167. , 3115167
  • Ferreiro, D.U., Komives, E.A., Wolynes, P.G., Frustration in biomolecules (2014) Quarterly reviews of biophysics, 47 (4), pp. 285-363. , 25225856
  • Main, E.R., Xiong, Y., Cocco, M.J., D’Andrea, L., Regan, L., Design of stable α-helical arrays from an idealized TPR motif (2003) Structure, 11 (5), pp. 497-508. , 12737816
  • Kajander, T., Cortajarena, A.L., Mochrie, S., Regan, L., Structure and stability of designed TPR protein superhelices: unusual crystal packing and implications for natural TPR proteins (2007) Acta Crystallographica Section D: Biological Crystallography, 63 (7), pp. 800-811. , 17582171
  • Binz, H.K., Stumpp, M.T., Forrer, P., Amstutz, P., Plückthun, A., Designing repeat proteins: well-expressed, soluble and stable proteins from combinatorial libraries of consensus ankyrin repeat proteins (2003) Journal of molecular biology, 332 (2), pp. 489-503. , 12948497
  • Stumpp, M.T., Forrer, P., Binz, H.K., Plückthun, A., Designing repeat proteins: modular leucine-rich repeat protein libraries based on the mammalian ribonuclease inhibitor family (2003) Journal of molecular biology, 332 (2), pp. 471-487. , 12948496
  • Ferreiro, D.U., Walczak, A.M., Komives, E.A., Wolynes, P.G., The energy landscapes of repeat-containing proteins: topology, cooperativity, and the folding funnels of one-dimensional architectures (2008) PLoS computational biology, 4 (5), p. e1000070. , 18483553
  • Parra, R.G., Espada, R., Sánchez, I.E., Sippl, M.J., Ferreiro, D.U., Detecting repetitions and periodicities in proteins by tiling the structural space (2013) The Journal of Physical Chemistry B, 117 (42), pp. 12887-12897. , 23758291
  • Espada, R., Parra, R.G., Sippl, M.J., Mora, T., Walczak, A.M., Ferreiro, D.U., Repeat Proteins challenge the concept of structural domains (2015) Biochemical Society Transactions, 43 (5), pp. 844-849. , 26517892
  • Frauenfelder, H., McMahon, B.H., Fenimore, P.W., Myoglobin: the hydrogen atom of biology and a paradigm of complexity (2003) Proceedings of the National Academy of Sciences, 100 (15), pp. 8615-8617. , 12861080
  • Morcos, F., Pagnani, A., Lunt, B., Bertolino, A., Marks, D.S., Sander, C., Direct-coupling analysis of residue coevolution captures native contacts across many protein families (2011) Proceedings of the National Academy of Sciences, 108 (49), pp. E1293-E1301. , 22106262
  • Ekeberg, M., Lövkvist, C., Lan, Y., Weigt, M., Aurell, E., Improved contact prediction in proteins: using pseudolikelihoods to infer Potts models (2013) Physical Review E, 87 (1), p. 12707. , 23410359
  • Ekeberg, M., Hartonen, T., Aurell, E., Fast pseudolikelihood maximization for direct-coupling analysis of protein structure from many homologous amino-acid sequences (2014) Journal of Computational Physics, 276, pp. 341-356
  • Balakrishnan, S., Kamisetty, H., Carbonell, J.G., Lee, S.I., Langmead, C.J., Learning generative models for protein fold families (2011) Proteins: Structure, Function, and Bioinformatics, 79 (4), pp. 1061-1078. , 21268112
  • Morcos, F., Jana, B., Hwa, T., Onuchic, J.N., Coevolutionary signals across protein lineages help capture multiple protein conformations (2013) Proceedings of the National Academy of Sciences, 110 (51), pp. 20533-20538. , 24297889
  • Cheng, R.R., Morcos, F., Levine, H., Onuchic, J.N., Toward rationally redesigning bacterial two-component signaling systems using coevolutionary information (2014) Proceedings of the National Academy of Sciences, 111 (5), pp. E563-E571. , 24449878
  • Sułkowska, J.I., Morcos, F., Weigt, M., Hwa, T., Onuchic, J.N., Genomics-aided structure prediction (2012) Proceedings of the National Academy of Sciences, 109 (26), pp. 10340-10345. , 22691493
  • Ovchinnikov, S., Kamisetty, H., Baker, D., Robust and accurate prediction of residue–residue interactions across protein interfaces using evolutionary information (2014) Elife, 3, p. e02030. , 24842992
  • Cheng, R.R., Raghunathan, M., Noel, J.K., Onuchic, J.N., Constructing sequence-dependent protein models using coevolutionary information (2016) Protein Science, 25 (1), pp. 111-122. , 26223372
  • Zahnd, C., Wyler, E., Schwenk, J.M., Steiner, D., Lawrence, M.C., McKern, N.M., A designed ankyrin repeat protein evolved to picomolar affinity to Her2 (2007) Journal of molecular biology, 369 (4), pp. 1015-1028. , 17466328
  • Cliff, M.J., Williams, M.A., Brooke-Smith, J., Barford, D., Ladbury, J.E., Molecular recognition via coupled folding and binding in a TPR domain (2005) Journal of molecular biology, 346 (3), pp. 717-732. , 15713458
  • Levy, R.M., Haldane, A., Flynn, W.F., Potts Hamiltonian models of protein co-variation, free energy landscapes, and evolutionary fitness (2017) Current Opinion in Structural Biology, 43, pp. 55-62. , 27870991
  • Contini, A., Tiana, G., A many-body term improves the accuracy of effective potentials based on protein coevolutionary data (2015) The Journal of chemical physics, 143 (2), p. 25103. , 26178131
  • Sutto, L., Marsili, S., Valencia, A., Gervasio, F.L., From residue coevolution to protein conformational ensembles and functional dynamics (2015) Proceedings of the National Academy of Sciences, 112 (44), pp. 13567-13572. , 26487681
  • Haldane, A., Flynn, W.F., He, P., Vijayan, R., Levy, R.M., Structural Propensities of Kinase Family Proteins from a Potts Model of Residue Co-Variation (2016) Protein Science, , 27241634
  • Figliuzzi, M., Jacquier, H., Schug, A., Tenaillon, O., Weigt, M., Coevolutionary landscape inference and the context-dependence of mutations in beta-lactamase TEM-1 (2015) Molecular biology and evolution, , 26446903
  • Hopf, TA, Ingraham, JB, Poelwijk, FJ, Springer, M, Sander, C, Marks, DS. Quantification of the effect of mutations using a global probability model of natural sequence variation. arXiv preprint arXiv:151004612. 2015; Schüler, A., Bornberg-Bauer, E., Evolution of Protein Domain Repeats in Metazoa (2016) Molecular Biology and Evolution, , 27671125
  • Espada, R., Parra, R.G., Mora, T., Walczak, A.M., Ferreiro, D.U., Capturing coevolutionary signals inrepeat proteins (2015) BMC bioinformatics, 16 (1), p. 207. , 26134293
  • Mosavi, L.K., Minor, D.L., Peng, Z., Consensus-derived structural determinants of the ankyrin repeat motif (2002) Proceedings of the National Academy of Sciences, 99 (25), pp. 16029-16034. , 12461176
  • Weigt, M., White, R.A., Szurmant, H., Hoch, J.A., Hwa, T., Identification of direct residue contacts in protein–protein interaction by message passing (2009) Proceedings of the National Academy of Sciences, 106 (1), pp. 67-72. , 19116270
  • Finkelstein, A.V., Badretdinov, A.Y., Gutin, A.M., Why do protein architectures have boltzmann-like statistics? (1995) Proteins: Structure, Function, and Bioinformatics, 23 (2), pp. 142-150. , 8592696
  • Krachler, A.M., Sharma, A., Kleanthous, C., Self-association of TPR domains: Lessons learned from a designed, consensus-based TPR oligomer (2010) Proteins: Structure, Function, and Bioinformatics, 78 (9), pp. 2131-2143. , 20455268
  • Cortajarena, A.L., Wang, J., Regan, L., Crystal structure of a designed tetratricopeptide repeat module in complex with its peptide ligand (2010) FEBS journal, 277 (4), pp. 1058-1066. , 20089039
  • Zhu, H., Sepulveda, E., Hartmann, M.D., Kogenaru, M., Ursinus, A., Sulz, E., Origin of a folded repeat protein from an intrinsically disordered ancestor (2016) eLife, 5, p. e16761. , 27623012
  • Turjanski, P., Parra, R.G., Espada, R., Becher, V., Ferreiro, D.U., Protein Repeats from First Principles (2016) Scientific reports, 6. , 27044676
  • DeVries, I., Ferreiro, D.U., Sánchez, I.E., Komives, E.A., Folding kinetics of the cooperatively folded subdomain of the IκBα ankyrin repeat domain (2011) Journal of molecular biology, 408 (1), pp. 163-176. , 21329696
  • Ferreiro, D.U., Cervantes, C.F., Truhlar, S.M., Cho, S.S., Wolynes, P.G., Komives, E.A., Stabilizing IκBα by “consensus” design (2007) Journal of molecular biology, 365 (4), pp. 1201-1216. , 17174335
  • Street, T.O., Bradley, C.M., Barrick, D., An improved experimental system for determining small folding entropy changes resulting from proline to alanine substitutions (2005) Protein science, 14 (9), pp. 2429-2435. , 16131666
  • Tang, K.S., Fersht, A.R., Itzhaki, L.S., Sequential unfolding of ankyrin repeats in tumor suppressor p16 (2003) Structure, 11 (1), pp. 67-73. , 12517341
  • Schymkowitz, J., Borg, J., Stricher, F., Nys, R., Rousseau, F., Serrano, L., The FoldX web server: an online force field (2005) Nucleic acids research, 33, pp. W382-W388. , 15980494
  • Dao, T.P., Majumdar, A., Barrick, D., Highly polarized C-terminal transition state of the leucine-rich repeat domain of PP32 is governed by local stability (2015) Proceedings of the National Academy of Sciences, 112 (18), pp. E2298-E2306. , 25902505
  • Björklund, ÅK., Ekman, D., Elofsson, A., Expansion of protein domain repeats (2006) PLoS Comput Biol, 2 (8), p. e114. , 16933986
  • Morcos, F., Schafer, N.P., Cheng, R.R., Onuchic, J.N., Wolynes, P.G., Coevolutionary information, protein folding landscapes, and the thermodynamics of natural selection (2014) Proceedings of the National Academy of Sciences, 111 (34), pp. 12408-12413. , 25114242
  • Bateman, A., Coin, L., Durbin, R., Finn, R.D., Hollich, V., Griffiths-Jones, S., The Pfam protein families database (2004) Nucleic acids research, 32, pp. D138-D141. , 14681378
  • UniProt: the universal protein knowledgebase (2017) Nucleic acids research, 45 (D1), pp. D158-D169. , 27899622
  • Li, W., Jaroszewski, L., Godzik, A., Tolerating some redundancy significantly speeds up clustering of large protein databases (2002) Bioinformatics, 18 (1), pp. 77-82. , 11836214


---------- APA ----------
Espada, R., Parra, R.G., Mora, T., Walczak, A.M. & Ferreiro, D.U. (2017) . Inferring repeat-protein energetics from evolutionary information. PLoS Computational Biology, 13(6).
---------- CHICAGO ----------
Espada, R., Parra, R.G., Mora, T., Walczak, A.M., Ferreiro, D.U. "Inferring repeat-protein energetics from evolutionary information" . PLoS Computational Biology 13, no. 6 (2017).
---------- MLA ----------
Espada, R., Parra, R.G., Mora, T., Walczak, A.M., Ferreiro, D.U. "Inferring repeat-protein energetics from evolutionary information" . PLoS Computational Biology, vol. 13, no. 6, 2017.
---------- VANCOUVER ----------
Espada, R., Parra, R.G., Mora, T., Walczak, A.M., Ferreiro, D.U. Inferring repeat-protein energetics from evolutionary information. PLoS Comput. Biol. 2017;13(6).