Quartz 4

Stability-activity trade-off during enzyme design and evolution is highly local and not global

Created Modified

Summary

Stability and function trade off during design, and usually substitutions boosting activity lead to decreases in stability (1). This is true of (antibodies) and enzymes. By contrast, (2) find no such tradeoff among sequences designed by ancestral sequence reconstruction, whi (3) also find no trade-off in a diverse pool of extant adenylate kinase variants, suggesting that this trade-off is highly local in nature and not “global” across a specific enzyme class.

Details

In enzymes, (4) find that residues in the first shell surrounding the active site contribute to stability and counteract destabilizing residues in the active site. On average, they found that mutating active site residues led to increased stability of on average 0.54 kcal/mol, compared to -0.37 kcal/mol for non-catalytic residues. In contrast, (5) find that there is no clear split between active-site and second-shell in stabilizing or destabilizing proteins

Figures

Ref (3)

1.
Tokuriki N, Stricher F, Serrano L, Tawfik DS. How Protein Stability and New Functions Trade Off. PLoS Computational Biology. 2008;4(2):e1000002. Available from: https://doi.org/10.1371/journal.pcbi.1000002
2.
Sennett MA, Beckett BC, Theobald DL. The most probable ancestral sequence reconstruction yields proteins without systematic bias in thermal stability or activity. openRxiv; 2023. Available from: https://doi.org/10.1101/2023.02.22.529562
3.
Muir DF, Asper GPR, Notin P, Posner JA, Marks DS, Keiser MJ, et al. Evolutionary-scale enzymology enables exploration of a rugged catalytic landscape. Science. 2025;388(6752). Available from: https://doi.org/10.1126/science.adu1058
4.
Hou Q, Rooman M, Pucci F. Enzyme Stability-Activity Trade-Off: New Insights from Protein Stability Weaknesses and Evolutionary Conservation. Journal of Chemical Theory and Computation. 2023;19(12):3664–71. Available from: https://doi.org/10.1021/acs.jctc.3c00036
5.
Zarifi N, Asthana P, Doustmohammadi H, Klaus C, Sanchez J, Hunt SE, et al. Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release. Nature Communications. 2025;16(1). Available from: https://doi.org/10.1038/s41467-025-63802-7

Graph View

Backlinks