Structure‐energy‐based predictions and network modelling of RAS opathy and cancer missense mutations

The Ras/ MAPK syndromes (‘ RAS opathies’) are a class of developmental disorders caused by germline mutations in 15 genes encoding proteins of the Ras/mitogen‐activated protein kinase ( MAPK ) pathway frequently involved in cancer. Little is known about the molecular mechanisms underlying the differences in mutations of the same protein causing either cancer or RAS opathies. Here, we shed light on 956 RAS opathy and cancer missense mutations by combining protein network data with mutational analyses based on 3D structures. Using the protein design algorithm FoldX, we predict that most of the missense mutations with destabilising energies are in structural regions that control the activation of proteins, and only a few are predicted to compromise protein folding. We find a trend that energy changes are higher for cancer compared to RAS opathy mutations. Through network modelling, we show that partly compensatory mutations in RAS opathies result in only minor downstream pathway deregulation. In summary, we suggest that quantitative rather than qualitative network differences determine the phenotypic outcome of RAS opathy compared to cancer mutations.