Structure-based machine-guided mapping of amyloid sequence space reveals uncharted sequence clusters with higher solubilities

Nat Commun. 2020 Jul 3;11(1):3314. doi: 10.1038/s41467-020-17207-3.


The amyloid conformation can be adopted by a variety of sequences, but the precise boundaries of amyloid sequence space are still unclear. The currently charted amyloid sequence space is strongly biased towards hydrophobic, beta-sheet prone sequences that form the core of globular proteins and by Q/N/Y rich yeast prions. Here, we took advantage of the increasing amount of high-resolution structural information on amyloid cores currently available in the protein databank to implement a machine learning approach, named Cordax (, that explores amyloid sequence beyond its current boundaries. Clustering by t-Distributed Stochastic Neighbour Embedding (t-SNE) shows how our approach resulted in an expansion away from hydrophobic amyloid sequences towards clusters of lower aliphatic content and higher charge, or regions of helical and disordered propensities. These clusters uncouple amyloid propensity from solubility representing sequence flavours compatible with surface-exposed patches in globular proteins, functional amyloids or sequences associated to liquid-liquid phase transitions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • Amyloid / chemistry*
  • Amyloid / metabolism
  • Amyloidogenic Proteins / chemistry*
  • Amyloidogenic Proteins / metabolism
  • Amyloidosis / metabolism
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Machine Learning
  • Models, Chemical*
  • Peptides / chemistry*
  • Peptides / metabolism
  • Protein Conformation
  • Protein Engineering / methods
  • Solubility


  • Amyloid
  • Amyloidogenic Proteins
  • Peptides