Multiscale molecular dynamics insights into the mechanical impact of skin cancer–associated actin mutations

Actin filaments serve as essential structural scaffolds whose mechanical integrity governs cellular function and cancer progression. Despite established links between actin mutations and oncogenesis, their quantitative nanomechanical consequences remain poorly defined, obscuring metastasis mechanisms. This study deployed integrated multiscale molecular dynamics (MD) simulations, combining all-atom (AA) and coarse-grained (CG) approaches, to decode how skin cancer–associated single-residue mutations (D288N, G44R, G168N, R41Q, R63Q) influence actin's structural and mechanical properties. Simulations revealed discernible but non‑catastrophic structural alterations in mutants – modest elevation in radius of gyration (Rg), slight expansion in solvent-accessible surface area (SASA), and reduced inter‑monomeric hydrogen bonding – with no evidence of filament disassembly or global unfolding. These subtle changes were associated with disproportionate mechanical failure, with tensile stiffness declining 12–22%, bending rigidity ( E I ) diminishing 2–62% (notably >60% loss in R41Q), and persistence length ( l p ) contracting 2–62%, aligning with experimental cancer-cell softening. Mutant filaments further exhibited viscoelastic deterioration under load, with marked elastic modulus reductions and prolonged retardation times. This apparent discordance between minor structural perturbations and major mechanical deficits highlights the extreme sensitivity of interfacial residues in force transmission. This computational approach offers insights into biophysical processes that may contribute to metastasis while identifying potential nanomechanical hotspots in the five actin mutants studied, suggesting that these specific mutations may alter actin's role from a structural element to a mechanopathological factor – a hypothesis requiring experimental validation.