Most mutations with no effect on stability are found near the surface of proteins

Summary

Most mutations are destabilizing, and most of those that aren’t are located on the surfaces of enzymes (1). The corollary is that most mutations on the surface have no effect; but this is not true of indels (2). Green fluorescent protein is an example where most mutations that affected function (fluorescence) were pointing inward; i.e., not on the protein surface (3).

See also

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

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.

Topolska M, Beltran A, Lehner B. Deep indel mutagenesis reveals the impact of amino acid insertions and deletions on protein stability and function. Nature Communications. 2025;16(1). Available from: https://doi.org/10.1038/s41467-025-57510-5

3.

Sarkisyan KS, Bolotin DA, Meer MV, Usmanova DR, Mishin AS, Sharonov GV, et al. Local fitness landscape of the green fluorescent protein. Nature. 2016;533(7603):397–401. Available from: https://doi.org/10.1038/nature17995