Role of structural and sequence information in the prediction of protein stability changes: comparison between buried and partially buried mutations

Predicting mutation-induced changes in protein stability is one of the grea test challenges in molecular biology, In this work, we analyzed the correla tion between stability changes caused by buried and partially buried mutati ons and changes in 48 physicochemical, energetic and conformational propert ies. We found that properties reflecting hydrophobicity strongly correlated with stability of buried mutations, and there was a direct relation betwee n the property values and the number of carbon atoms. Classification of mut ations based on their location within helix, strand, turn or coil segments improved the correlation of mutations with stability. Buried mutations with in beta-strand segments correlated better than did those in alpha-helical s egments, suggesting stronger hydrophobicity of the beta-strands. The stabil ity changes caused by partially buried mutations in ordered structures (hel ix, strand and turn) correlated most strongly and were mainly governed by h ydrophobicity, Due to the disordered nature of coils, the mechanism underly ing their stability differed from that of the other secondary structures: t he stability changes due to mutations within the coil were mainly influence d by the effects of entropy. Further classification of mutations within coi ls, based on their hydrogen-bond forming capability, led to much stronger c orrelations. Hydrophobicity was the major factor in determining the stabili ty of buried mutations, whereas hydrogen bonds, other polar interactions an d hydrophobic interactions were all important determinants of the stability of partially buried mutations. Information about local sequence and struct ural effects were more important for the prediction of stability changes ca used by partially buried mutations than for buried mutations; they strength ened correlations by an average of 27% among all data sets.