Nature disfavors sequences of alternating polar and non-polar amino acids: implications for amyloidogenesis

J Mol Biol. 2000 Mar 3;296(4):961-8. doi: 10.1006/jmbi.2000.3514.


Recent experiments with combinatorial libraries of de novo proteins have demonstrated that sequences designed to contain polar and non-polar amino acid residues arranged in an alternating pattern form fibrillar structures resembling beta-amyloid. This finding prompted us to probe the distribution of alternating patterns in the sequences of natural proteins. Analysis of a database of 250,514 protein sequences (79,708,024 residues) for all possible binary patterns of polar and non-polar amino acid residues revealed that alternating patterns occur significantly less often than other patterns with similar compositions. The under-representation of alternating binary patterns in natural protein sequences, coupled with the observation that such patterns promote amyloid-like structures in de novo proteins, suggests that sequences of alternating polar and non-polar amino acids are inherently amyloidogenic and consequently have been disfavored by evolutionary selection.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acids / chemistry*
  • Amyloid / chemistry*
  • Amyloidosis / metabolism*
  • Databases, Factual
  • Humans
  • Protein Engineering


  • Amino Acids
  • Amyloid