Crick’s sequence hypothesis - a review

ABSTRACT

Health care based on gene sequencing and genomics is increasingly becoming a reality: it is timely to review Crick’s sequence hypothesis for its fitness for this purpose. The sequence hypothesis is central to the prediction and correction of disease traits from gene sequence information. Considerable success in this respect has been achieved for rare diseases, but for the dominant part of the human disease burden, common diseases, little progress has been made since the completion of the sequencing of the human genome. It is argued here that the sequence hypothesis, namely the assumption that peptides will fold spontaneously to the native state protein, thus retaining the information coded in the originating genes, is not supported by a realistic physics-based assessment of the peptide to protein folding process.

KEYWORDS:

• Peptide folding
• misfolded proteins
• mutation
• GWAS
• moonlighting proteins
• maximum entropy
• chaperones: native state

Acknowledgments

I gratefully acknowledge constructive discussions with Arto Annila, John Berriman (particularly for sharing his extensive expertise and drawing my attention to the phenomenon of moonlighting proteins) and Hans Edelmann.

Disclosure statement

No potential conflict of interest was reported by the author.

Notes

1. This is another way of viewing Anfinsen’s experiment with ribonuclease. He observed the ribonuclease peptide progressing from the state of maximum free energy towards the state of maximum entropy, the stationary, in the context of the folding process, state, or native state structurally, at which point the ribonuclease activity (information) appeared. Other activities (information) may have appeared at the local maximum entropies of many misfolded peptides, but had he been able to detect them, they would have been transitory in his experiment. This perspective generalises, what at first sight appears to be, a ‘specific case’ study testing Crick’s sequence hypothesis, although he makes no reference to Crick.

2. https://www.biorxiv.org/content/early/2018/12/04/485441.