Protein destabilization by amino acid substitutions is proposed to play a prominent role in widespread inherited human disorders, not just those known to involve protein misfolding and aggregation. To test this hypothesis, we computationally evaluate the effects on protein stability of all possible amino acid substitutions in 20 disease-associated proteins with multiple identified pathogenic missense mutations. For 18 of the 20 proteins studied, substitutions at known positions of pathogenic mutations are significantly more likely to destabilize the native protein fold (as indicated by more positive values of ΔΔG). Thus, positions identified as sites of disease-associated mutations, as opposed to non-disease-associated sites, are predicted to be more vulnerable to protein destabilization upon amino acid substitution. This finding supports the notion that destabilization of native protein structure underlies the pathogenicity of broad set of missense mutations, even in cases where reduced protein stability and/or aggregation are not characteristic of the disease state.
Supercharging the external residues of natural proteins has been shown to increase solubility and thermal stability while retaining protein function. In this work we elucidate the effects of supercharging exterior residues on the solubility, folding propensities, and ligand binding properties of mutants of the de novo designed heme-binding protein HHHH.
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