Microsecond molecular dynamics of SOD1 variants suggest a structural basis for divergent ALS clinical outcomes

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive motor neuron degeneration. The SOD1 gene, which encodes a protein, is the second most common genetic cause of ALS. Mutations in SOD1 result in different clinical profiles, with the A4V variant leading to an aggressive form of the disease with a median survival of around one year, while the H46R variant is associated with a mild, slowly progressive course and the I113T variant exhibits an intermediate phenotype.

The reasons behind these diverse clinical outcomes remain unclear. To investigate this, researchers conducted extensive classical molecular dynamics simulations of the wild-type SOD1 and the three ALS-associated variants - A4V, H46R, and I113T - in their apo monomeric state.

By analyzing the structural stability, global compactness, conformational flexibility, collective motions between residues, and estimation of free energy, the research team discovered distinct dynamic behaviors among the variants. These differences in structural stability, local flexibility, and intramolecular interactions suggest that certain structural regions contribute differently to protein dysfunction and could be key elements in understanding the relationship between molecular dynamic properties and the varying clinical severity associated with these variants.

Notably, the H46R variant exhibited remarkable structural stability across all analytical levels, the lowest global deviation, minimal local flexibility, the strongest internal dynamic coordination, and the deepest and most confined free energy basins. This multi-layered evidence of structural restraint offers a compelling mechanistic basis for the mild and slowly progressive clinical course of H46R ALS.

In essence, enhanced conformational rigidity, rather than bulk destabilization, is the defining biophysical feature of this variant. Consequently, its pathogenic mechanism appears to operate through a route fundamentally distinct from the aggregation-driven toxicity seen in more aggressive SOD1-ALS mutations.