Abstract
IT is rare for amino-acid substitutions on the surface of proteins to have large stabilizing or destabilizing effects1. Nevertheless, one substitution of this type, the Tyr 26 → Cys mutation in λ Cro, increases the melting temperature of the protein by 11°C and the stability by 2.2 kcal mol−1 (ref. 2). Here we show that the stability of Cro can be increased by many different amino-acid substitutions at position 26, with increasing stability showing a good correlation with decreasing side-chain hydrophobicity. As Tyr 26 is hyper-exposed to solvent in the Cro crystal structure3,4, we suggest that wild-type and variant proteins with other hydrophobic side chains at position 26 are destabilized as a result of a reverse hydrophobic effect caused by the side chain being more exposed to solvent in the native than in the denatured state.
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References
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Pakula, A., Sauer, R. Reverse hydrophobic effects relieved by amino-acid substitutions at a protein surface. Nature 344, 363–364 (1990). https://doi.org/10.1038/344363a0
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DOI: https://doi.org/10.1038/344363a0
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