Machine learning integration for predicting the effect of single amino acid substitutions on protein stability

Background: Computational prediction of protein stability change due to single-site amino acid substitutions is of interest in protein design and analysis. We consider the following four ways to improve the performance of the currently available predictors: (1) We include additional sequence-and structure-based features, namely, the amino acid substitution likelihoods, the equilibrium fluctuations of the alpha- and beta-carbon atoms, and the packing density. (2) By implementing different machine learning integration approaches, we combine information from different features or representations. (3) We compare classification vs. regression methods to predict the sign vs. the output of stability change. (4) We allow a reject option for doubtful cases where the risk of misclassification is high.