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Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins

Nature Biotechnology volume 22, pages 1302–1306 (2004)Cite this article

Abstract

We have developed a statistical mechanics algorithm, TANGO, to predict protein aggregation. TANGO is based on the physico-chemical principles of β-sheet formation, extended by the assumption that the core regions of an aggregate are fully buried. Our algorithm accurately predicts the aggregation of a data set of 179 peptides compiled from the literature as well as of a new set of 71 peptides derived from human disease-related proteins, including prion protein, lysozyme and β2-microglobulin. TANGO also correctly predicts pathogenic as well as protective mutations of the Alzheimer β-peptide, human lysozyme and transthyretin, and discriminates between β-sheet propensity and aggregation. Our results confirm the model of intermolecular β-sheet formation as a widespread underlying mechanism of protein aggregation. Furthermore, the algorithm opens the door to a fully automated, sequence-based design strategy to improve the aggregation properties of proteins of scientific or industrial interest.

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Figure 1: Schematic representation of the predicted aggregating regions in some proteins derived from the literature.
Figure 2: Prediction of aggregation in the Alzheimer β-peptide.
Figure 3: TANGO performance on a full-length protein.

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Acknowledgements

We thank Jesper Borg for helpful discussions. We are also grateful to Fabrizio Chiti for pointing us to data on amyloid forming sequences. J.S. and F.R. held a Prize Traveling Fellowship of the Wellcome Trust while at EMBL. A.M.F.E. was funded through a Marie Curie Fellowship from the European Union. This work was partly supported by an EU Training and Mobility of Researchers grant (EU Network on amyloid fibril formation, CT2-00241).

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Authors and Affiliations

  1. European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, D-69117, Germany

    Ana-Maria Fernandez-Escamilla & Luis Serrano

  2. SWITCH Laboratory, Flemish Institute for Biotechnology, Vrije Universiteit Brussel, Pleinlaan 2, Brussel, 1050, Belgium

    Frederic Rousseau & Joost Schymkowitz

Authors
  1. Ana-Maria Fernandez-Escamilla
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  2. Frederic Rousseau
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  4. Luis Serrano
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Correspondence to Luis Serrano.

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Supplementary information

Supplementary Fig. 1

Control measurements on the aggregation of peptides. (PDF 85 kb)

Supplementary Table 1

Dataset derived from literature: Comparison between TANGO predicted aggregation and experimental information available in the literature on peptides derived from 21 proteins. (PDF 143 kb)

Supplementary Table 2

Dataset measured in our laboratory: Comparison between TANGO aggregation score and newly acquired experimental data using CD spectroscopy on the aggregation of peptides derived from the sequence of human prion protein, human lysozyme and β-microglobulin. (PDF 74 kb)

Supplementary Note 1 (PDF 92 kb)

Supplementary Note 2 (PDF 135 kb)

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Fernandez-Escamilla, AM., Rousseau, F., Schymkowitz, J. et al. Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat Biotechnol 22, 1302–1306 (2004). https://doi.org/10.1038/nbt1012

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