Fitness of unregulated human Ras mutants modeled by implementing computational mutagenesis and machine learning techniques

Abstract

Ras proteins play a pivotal role as oncogenes by participating in diverse signaling events, including those linked to cell growth, differentiation, and proliferation. Using experimental fitness data and implementing artificial intelligence and a computational mutagenesis technique, we developed models that reliably predict fitness for all single residue mutants of H- ras proto-oncogene protein p21. The computational mutagenesis generated a feature vector of protein structural changes for each variant, and these data correlated well with fitness. Random forest classification and tree regression machine learning algorithms were implemented for training predictive models. Cross-validations were used to evaluate model performance, and control experiments were performed to assess statistical significance. Classification models revealed a balanced accuracy rate as high as 82%, with a Matthew's correlation of 0.63, and an area under ROC curve of 0.90. Similarly, regression models displayed Pearson's correlation reaching 0.79. On the other hand, control data sets led to performance values consistent with random guessing. Comparisons with several related state-of-the-art methods reflected favorably on our trained models. This H-Ras proof-of-principle study suggests a complementary approach for understanding mechanisms with which other proteins are involved in oncogenesis, including related Ras isoforms, and for providing useful insights into designing future diagnostic and treatment modalities.