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Data from: The emergence of novel versus known three-dimensional structures from random sequences

Yang, Hyunjun1; Yang, Rose2; Wu, Yibing2; DeGrado, William2

Published Jun 16, 2026 on Dryad. https://doi.org/10.5061/dryad.vmcvdnd4m

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Abstract

It has been hypothesized that random sequences are unlikely to fold into proteins of the length of globular proteins, but that shorter repeated random sequences are more likely to adopt folded conformations, which were predecessors to modern proteins.  To test this idea, we used structure prediction methods to determine the foldability of approximately 120-residue sequences composed of 5- to 60-residue random repeats.  With repeats of less than 30-residues, sequences were discovered that fold with high confidence (1 - 12%).  The most frequent structures were β-solenoids and repeating β-hairpins, although helical bundles were observed when insertions or deletions were included between blocks of repeating sequences.  We also observed a new super-secondary structure consisting of a tightly wound α-helical screw, and experimentally confirmed its stability and structure by CD spectroscopy and X-ray crystallography.  Thus, folding programs are able to predict repeating structures that are well out of the distribution of structures upon which they were trained.  However, very few random sequences with 60-residue repeats or lacking repeats altogether were predicted to fold, and the small number of structures we observed were representative of the already established major classes of tertiary structures; greater sampling would be needed to discover novel structures from a random distribution.  These studies validate previous predictions that proteins evolved through the repetition and assortment of short peptide sequences.