Computational prediction of pathogenic properties of SOD1 mutants which are associated with amyotrophic lateral sclerosis

Intracellular protein aggregation is one of the causes of many neurodegenerative diseases. In particular, mutations in the SOD1 gene are associated with the familial form of amyotrophic lateral sclerosis (ALS). We have previously proposed a regression model that predicts the survival of patients with ALS who are carriers of mutations in the SOD1 protein. This model was built on the basis of the analysis of the stability of hydrogen bonds forming in SOD1 mutants when simulated by the molecular dynamics (MD). In the present work, this regression model has been improved by taking into account the new characteristic of hydrogen bonds, reflecting the conservativeness index of the hydrogen bond in the space of conformational states of the protein. The calculation of conformational conservatism of hydrogen bonds, carried out using elastic network (EN) models, made it possible to increase the correlation coefficient between the predicted using the new model and the observed survival values of patients with mutations in SOD1 (R = 0.92).