RT Journal Article
SR Electronic
T1 Identification of pathogenic missense mutations using protein stability predictors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.11.146068
DO 10.1101/2020.06.11.146068
A1 Lukas Gerasimavicius
A1 Xin Liu
A1 Joseph A Marsh
YR 2020
UL http://biorxiv.org/content/early/2020/06/12/2020.06.11.146068.abstract
AB Attempts at using protein structures to identify disease-causing mutations have been dominated by the idea that most pathogenic mutations are disruptive at a structural level. Therefore, computational stability predictors, which assess whether a mutation is likely to be stabilising or destabilising to protein structure, have been commonly used when evaluating new candidate disease variants, despite not having been developed specifically for this purpose. We therefore tested 12 different stability predictors for their ability to discriminate between pathogenic and putatively benign missense variants. We find that one method, FoldX, considerably outperforms all others in the identification of disease variants. Moreover, we demonstrate that employing absolute energy change scores improves performance of nearly all predictors. Importantly, however, we observe that the utility of computational stability predictors is highly heterogeneous across different proteins, and that they are all are inferior to the best performing variant effect predictors for identifying pathogenic mutations. We suggest that this is largely due to alternate molecular mechanisms other than protein destabilisation underlying many pathogenic mutations. Thus, better ways of incorporating protein structural information and molecular mechanisms into computational variant effect predictors will be required for improved disease variant prioritisation.Competing Interest StatementThe authors have declared no competing interest.