Predicting protein stability changes upon mutation using database-derived potentials: solvent accessibility determines the importance of local versus non-local interactions along the sequence.
For 238 mutations of residues totally or partially buried in the protein core, we estimate the folding free energy changes upon mutation using database-derived potentials and correlate them with the experimentally measured ones. Several potentials are tested, representing different kinds of interactions. Local interactions along the chain are described by torsion potentials, based on propensities of amino acids to be associated with backbone torsion angle domains. Non-local interactions along the sequence are represented by distance potentials, derived from propensities of amino acid pairs or triplets to be at a given spatial distance. We find that for the set of totally buried residues, the best performing potential is a combination of a distance potential and a torsion potential weighted by a factor of 0.4; it yields a correlation coefficient between computed and measured changes in folding free energy of 0.80. For mutations of partially buried residues, the best potential is a combination of a torsion potential and a distance potential weighted by a factor of 0.7, and for the previously analysed mutations of solvent accessible residues, it is a torsion potential taken individually; the respective correlation coefficients reach 0.82 and 0.87. These results show that distance potentials, dominated by hydrophobic interactions, represent best the main interactions stabilizing the protein core, whereas torsion potentials, describing local interactions along the chain, represent best the interactions at the protein surface. The prediction accuracy reached by the distance potentials is, however, lower than that of the torsion potentials. A possible reason for this is that distance potentials would not describe correctly the effect on protein stability due to cavity formation upon mutating a large into a small amino acid. Last but not least, our results indicate that although local interactions, responsible for secondary structure formation, do not dominate in the protein core, they are not negligible for all that. They have a significant weight in the delicate balance between all the interactions that ensure protein stability.
Gilis
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UCMB, Université Libre de Bruxelles, CP160/16 av. F. Roosevelt 50, Brussels, 1050, Belgium.
Rooman
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D000818:Animals; D004795:Enzyme Stability; D006801:Humans; D009154:Mutation / Q000502:physiology*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D012997:Solvents; D013816:Thermodynamics
D011506:Proteins; D012997:Solvents