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

Recent experiments with combinatorial libraries of de novo proteins have de monstrated that sequences designed to contain polar and non-polar amino aci d residues arranged in an alternating pattern form fibrillar structures res embling beta-amyloid. This finding prompted us to probe the distribution of alternating patterns in the sequences of natural proteins. Analysis of a d atabase of 250,514 protein sequences (79,708,024 residues) for all possible binary patterns of polar and non-polar amino acid residues revealed that a lternating patterns occur significantly less often than other patterns with similar compositions. The under-representation of alternating binary patte rns in natural protein sequences, coupled with the observation that such pa tterns promote amyloid-like structures in de novo proteins, suggests that s equences of alternating polar and non-polar amino acids are inherently amyl oidogenic and consequently have been disfavored by evolutionary selection. (C) 2000 Academic Press.