PremPS: Predicting the impact of missense mutations on protein stability

Computational methods that predict protein stability changes induced by missense mutations have made a lot of progress over the past decades. Most of the available methods however have very limited accuracy in predicting stabilizing mutations because existing experimental sets are dominated by mutations reducing protein stability. Moreover, few approaches could consistently perform well across different test cases. To address these issues, we developed a new computational method PremPS to more accurately evaluate the effects of missense mutations on protein stability. The PremPS method is composed of only ten evolutionary- and structure-based features and parameterized on a balanced dataset with an equal number of stabilizing and destabilizing mutations. A comprehensive comparison of the predictive performance of PremPS with other available methods on nine benchmark datasets confirms that our approach consistently outperforms other methods and shows considerable improvement in estimating the impacts of stabilizing mutations. A protein could have multiple structures available, and if another structure of the same protein is used, the predicted change in stability for structure-based methods might be different. Thus, we further estimated the impact of using different structures on prediction accuracy, and demonstrate that our method performs well across different types of structures except for low-resolution structures and models built based on templates with low sequence identity. PremPS can be used for finding functionally important variants, revealing the molecular mechanisms of functional influences and protein design. PremPS is freely available at , which allows to do large-scale mutational scanning and takes about four minutes to perform calculations for a single mutation per protein with similar to 300 residues and requires similar to 0.4 seconds for each additional mutation. Author summary The development of computational methods to accurately predict the impacts of amino acid substitutions on protein stability is of paramount importance for the field of protein design and understanding the roles of missense mutations in disease. However, most of the available methods have very limited predictive accuracy for mutations increasing stability and few could consistently perform well across different test cases. Here we present a new computational approach PremPS, which is capable of predicting the effects of single point mutations on protein stability. PremPS employs only ten evolutionary- and structure-based features and is trained on a symmetrical dataset consisting of the same number of cases of stabilizing and destabilizing mutations. Our method was tested against numerous blind datasets and shows a considerable improvement especially in evaluating the effects of stabilizing mutations, outperforming previously developed methods. PremPS is freely available as a user-friendly web server at , which is fast enough to handle the large number of cases.