Stability Curve Prediction of Homologous Proteins Using Temperature-Dependent Statistical Potentials

The unraveling and control of protein stability at different temperatures is a fundamental problem in biophysics that is substantially far from being quantitatively and accurately solved, as it requires a precise knowledge of the temperature dependence of amino acid interactions. In this paper we attempt to gain insight into the thermal stability of proteins by designing a tool to predict the full stability curve as a function of the temperature for a set of 45 proteins belonging to 11 homologous families, given their sequence and structure, as well as the melting temperature () and the change in heat capacity () of proteins belonging to the same family. Stability curves constitute a fundamental instrument to analyze in detail the thermal stability and its relation to the thermodynamic stability, and to estimate the enthalpic and entropic contributions to the folding free energy. In summary, our approach for predicting the protein stability curves relies on temperature-dependent statistical potentials derived from three datasets of protein structures with targeted thermal stability properties. Using these potentials, the folding free energies () at three different temperatures were computed for each protein. The Gibbs-Helmholtz equation was then used to predict the protein's stability curve as the curve that best fits these three points. The results are quite encouraging: the standard deviations between the experimental and predicted 's, 's and folding free energies at room temperature () are equal to 13 , 1.3 ) and 4.1 , respectively, in cross-validation. The main sources of error and some further improvements and perspectives are briefly discussed.Author Summary: The prediction of protein stability remains one of the key goals of protein science. Despite the significant efforts of the last decades, faster and more accurate stability predictors on the proteomic-wide scale are currently demanded. The determination and control of protein stability are indeed fundamental steps on the path towards de novo design. In this paper we develop a method for predicting the stability curve of proteins. This curve encodes the temperature dependence of the folding free energy (). Its knowledge is important in the study of protein stability since all the thermodynamic parameters characterizing the folding transition can be extracted from it. Our prediction method is based on temperature-dependent mean force potentials and uses the tertiary structure of the target protein as well as the melting temperature () and the heat capacity change () of some other proteins belonging to the same family. From the predicted stability curves, the , the and the at room temperature can be inferred. The predictions obtained are compared with experimental data and show reasonable performances.