Structural and dynamic properties of mutant SOD1 proteins associated with amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which affects motor neurons in the brain and spinal cord and leads to patients’ death. One of the causes of motor neuron degeneration and death is the formation of intracellular aggregates by a mutant SOD1 protein. Recently, it has been shown that the survival time of ALS patients with a specific mutation in the SOD1 gene is inversely correlated to the thermodynamic stability of the SOD1 mutant protein. In the present paper, we hypothesize that mutant SOD1 aggregation can be facilitated by not only the destabilization due to the breakage of the hydrogen bond but also the formation of new hydrogen bonds, which can stabilize intermediate pathogenic conformations of the mutant SOD1 protein. Frequencies of hydrogen bond occurrence in the protein structure are estimated by molecular dynamics simulations. It is shown that the regression model based on frequencies of hydrogen bond occurrence is significantly better correlated to patients’ survival time (R = 0.89, p < 0.00001) than the estimation based on thermodynamic stability analysis of mutant SOD1 proteins.