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Preprint WatchModerateSeptember 2nd, 2026

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

Refaee, A. A.; Milanetti, E.; Roeder, K.; Ruocco, G.; Iacoangeli, A.

Microsecond molecular dynamics of apo monomeric SOD1 show that A4V, H46R and I113T variants differ in structural stability and conformational flexibility, offering a structural basis for their divergent clinical severity.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint uses microsecond molecular dynamics simulations to argue that A4V, H46R and I113T SOD1 variants occupy distinct conformational regimes, and that those differences map onto the wide spread in clinical severity between the variants. The Claidex record for SOD1 contains one documented failure, mt-1186-oral-edaravone-sod1-als-phase3-futility, an oral edaravone Phase 3 stopped for futility. The connection is a population one rather than a mechanistic overlap. If genotype-linked structural behaviour drives a large share of the variance in ALS progression rate, then unstratified ALS trials are averaging over patient groups whose natural histories differ by roughly a year of median survival, which inflates the sample size needed to detect any effect. The work is computational and does not include patient data, so it proposes a stratification hypothesis without validating one. It is a reason to treat SOD1 genotype as a prespecified stratification factor rather than a subgroup afterthought.

Abstract excerpt

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive motor neuron degeneration. Mutations in the SOD1 gene represent the second most common genetic cause of ALS (ALS), and distinct SOD1 missense variants present with markedly different clinical profiles. A4V leads to an aggressive form of the disease (median survival [~]1y), H46R confers a mild, slowly progressive course and I113T exhibits an intermediate phenotype. The molecular basis by which these mutations produce divergent clinical outcomes remains poorly understood. We performed extensive classical molecular dynamics simulations of wild-type SOD1 and the three ALS-associated variants in the apo monomeric state to attempt to investigate the mechanisms behind such phenotypic differences. Structural stability, global compactness, and conformational flexibility, as well as analysis of collective motions between residues and estimation of free energy, were assessed. The H46R, A4V, and I113T variants exhibited distinct dynamic behaviours, highlighting differences in structural stability, local flexibility, and intramolecular interactions. These findings suggest that specific structural regions may contribute differently to protein dysfunction and could represent key elements for understanding the relationship between molecular dynamic properties and the differing clinical severity associated with these variants. Most strikingly, H46R exhibited exceptional structural stability across every analytical level, the lowest global deviation, most attenuated local flexibility, strongest internal dynamic coordination, and the deepest, most confined free energy basins of any system examined. This convergent multi-layered evidence of structural restraint provides a compelling mechanistic basis for the mild and slowly progressive clinical course of H46R ALS, suggesting that enhanced conformational rigidity, rather than bulk destabilisation, is the defining biophysical feature of this variant, and that its pathogenic mechanism operates through a route fundamentally decoupled from the aggregation-driven toxicity that characterises the more aggressive SOD1-ALS mutations.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.