Molecular force gates regulate mechanical transmission across the nuclear envelope

Abstract The LINC (linker of nucleoskeleton and 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 provide computational evidence that a key disulfide bond (SUN2 Cys563 to KASH2 Cys6862) and specific residues within the KASH β strand interaction motif (KASH6875, KASH6877) act as distinct mechanical elements during force transmission across the SUN and KASH interface. Leveraging this framework, we show that the disulfide bond and the β sheet network contribute unequally: removing the disulfide reduces both sustained and peak force transmission approximately twofold, whereas disrupting the β sheet network leaves peak force largely intact while altering interfacial coupling and the duration over which load is borne. Localized molecular changes therefore reshape mechanical coupling to the nucleus through distinct routes rather than through a single graded loss of force. Such altered LINC mechanics may be relevant to laminopathies, including Hutchinson Gilford Progeria Syndrome (HGPS), in which defective nuclear lamina compromises force transmission; however, implications for specific diseases remain speculative and require experimental validation. By resolving how distinct molecular contacts contribute to force transmission in space and sequence, this work establishes a framework for dissecting mechanical coupling at protein interfaces under load. These findings provide a foundation for future studies aimed at experimentally testing how individual interface interactions govern nuclear force transmission, a prerequisite for therapeutically targeting LINC mechanics. More broadly, the force gate framework may guide strategies to modulate interfaces that bear mechanical loads in other mechanically regulated proteins. Together, these findings establish a computational framework for investigating force transmission at mechanically loaded protein interfaces and provide experimentally testable predictions for future studies.