Structural dynamics is a determinant of the functional significance of missense variants

Accurate evaluation of the effect of point mutations on protein function is essential to assessing the genesis and prognosis of many inherited diseases and cancer types. Currently, a wealth of computational tools has been developed for pathogenicity prediction. Two major types of data are used to this aim: sequence conservation/ evolution and structural properties. Here, we demonstrate in a systematic way that another determinant of the functional impact of missense variants is the protein's structural dynamics. Measurable improvement is shown in pathogenicity prediction by taking into consideration the dynamical context and implications of the mutation. Our study suggests that the class of dynamics descriptors introduced here may be used in conjunction with existing features to not only increase the prediction accuracy of the impact of variants on biological function, but also gain insight into the physical basis of the effect of missense variants.