Fitness prediction

Essential proteins are more thermostable and over-expressed than non-essential proteins

Diego del Alamo

24 Mar 2026 — 2 min read

Several properties of proteins have a sigmoid-like effect on cellular fitness. Thermostability is one of them: beyond a certain threshold, increases in protein thermostability confer no benefit, and decreases impose no penalty^[1]:

This concept, termed the principle of marginal stability^[2], is somewhat contradicted by the observation that essential proteins tend to be more thermostable than non-essential proteins from the same proteome^[3]:

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A recent report observed an analogous result for protein expression, showing that essential proteins are more likely to be overexpressed than non-essential proteins^[4]:

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This result reinforces the idea that, despite the sigmoid-like effect of both properties on overall cellular fitness, natural selection favors genomes that slightly over-optimize genes encoding essential proteins.

References

Sarkisyan, K. S., Bolotin, D. A., Meer, M. V., Usmanova, D. R., Mishin, A. S., Sharonov, G. V., Ivankov, D. N., Bozhanova, N. G., Baranov, M. S., Soylemez, O., Bogatyreva, N. S., Vlasov, P. K., Egorov, E. S., Logacheva, M. D., Kondrashov, A. S., Chudakov, D. M., Putintseva, E. V., Mamedov, I. Z., Tawfik, D. S., … Kondrashov, F. A. (2016). Local fitness landscape of the green fluorescent protein. Nature, 533(7603), 397–401. https://doi.org/10.1038/nature17995 ↩︎
Goldstein R. A. (2011). The evolution and evolutionary consequences of marginal thermostability in proteins. Proteins, 79(5), 1396–1407. https://doi.org/10.1002/prot.22964 ↩︎
Leuenberger, P., Ganscha, S., Kahraman, A., Cappelletti, V., Boersema, P. J., von Mering, C., Claassen, M., & Picotti, P. (2017). Cell-wide analysis of protein thermal unfolding reveals determinants of thermostability. Science, 355(6327). https://doi.org/10.1126/science.aai7825 ↩︎
Choi, H. J., Lo, T. W., Cutler, K. J., Huang, D., Will, W. R., & Wiggins, P. A. (2026). Protein overabundance is driven by growth robustness. Science Advances, 12(12). https://doi.org/10.1126/sciadv.adz9623 ↩︎

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References

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Flow matching and diffusion perform comparably on biomolecular structure prediction

Not all high-fitness sequences have plausible evolutionary paths from lower-fitness starting points via sequential introduction of mutations

Conformational entropy could still matter in miniprotein binder design

Glutamate- and lysine-rich designs are susceptible to expression failure resulting from adenosine-rich sequences