Enzymatic N-deacylation is the predicted membrane-disruption switch for sphingomyelin: a falsifiable in-silico framework for sphingolipid vulnerability in ALS.

Sphingolipid dysregulation is an emerging feature of amyotrophic lateral sclerosis (ALS), but no systematic method separates species that may worsen axon-myelin membrane integrity from matter that may counteract it. We present an in-silico framework classifying sphingolipids and designed derivatives as candidate membrane-disruptive or candidate protective species, scored against real biological referents using externally published tools rather than a bespoke composite. Its central finding concerns a single, chemically defined difference in lipid state. In coarse-grained (MARTINI 3) molecular dynamics with three independent replicates per system, intact palmitoyl-sphingomyelin is indistinguishable from a pure-POPC bilayer (leaflet-mean Δ thickness + 0.001 nm, 95% CI brackets zero), whereas the modeled N-deacylated form thins it in every replicate (Δ=-0.043 nm, [- 0.046, - 0.041]), tracking a lyso-phosphatidylcholine detergent control (-0.083 nm, [- 0.087, - 0.080]) on two concordant estimators. Because only one lyso-sphingolipid is parameterized in public MARTINI 3, N-deacylation is not established here as a class-wide effect. Across eleven ALS studies (2021-2026), six report elevated serine-palmitoyltransferase (SPT) pathway sphingolipids, all in monogenic SPTLC1/SPTLC2 cohorts, whereas sporadic cohorts show disturbance without a shared direction. Because the simulations do not address whether this species is produced, accumulates, or reaches pathological concentrations in ALS tissue, we present the ALS connection as hypothesis-generating rather than direct evidence. Separately, an explicitly exploratory arm reports two designed modulators with predicted target engagement (Boltz-2) and an ADMET triage of their liabilities. The primary contribution is the membrane result with a wet-lab panel that makes it falsifiable.