Molecular Force Gates Regulate SUN–KASH Mechanics and Nuclear Force Transmission: DATA

The LINC (Linker of Nucleus to Cytoskeleton) complex is a central mechanotransductive apparatus that physically couples cytoskeletal forces to the nuclear interior, thereby regulating nuclear architecture, chromatin organization, and downstream signaling. Using atomistic molecular dynamics simulations, we identify and characterize “force gates” within the LINC complex—structural interactions that maintain mechanical connectivity under load. By introducing targeted mutations into the KASH peptide and SUN protein, we reveal that a crucial disulfide bond (SUN563–KASH6862) and specific residues within the KASH β-strand interaction motif (KASH6875, KASH6877) are indispensable for robust force transmission and residue-level structural cohesion. Leveraging this framework for visualizing force propagation, we demonstrate how disruption of these molecular force gates mimics mechanotransduction defects characteristic of Hutchinson–Gilford Progeria Syndrome (HGPS). In HGPS, a silent LMNA mutation produces progerin, a pathogenic lamin A variant that compromises nuclear mechanics and load redistribution. Our findings suggest that modulating force gate function within the LINC complex may partially compensate for impaired lamina structure, offering a new mechanobiology-based therapeutic strategy. By conceptualizing essential structural contacts as targets analogous to enzymatic catalytic sites, this work establishes a foundation for structure-guided interventions aimed at restoring mechanical resilience in laminopathies. Future experimental validation will be critical to translate these computational insights toward clinical applications.