Inter-lamin interactions control meshwork topologyin a polymer-gel model of nuclear lamina
The nuclear lamina is a specialized two-dimensional filamentous polymer meshwork that provides structural integrity and elasticity to the nucleus while orchestrating diverse cellular processes. Composed of interacting A- and B-type lamin networks, this structure undergoes tightly regulated self-assembly that is frequently perturbed by disease-causing mutations such as those observed in laminopathies or cardiomyopathies. However, because filament assembly, peripheral adsorption of lamins, and network branching occur concurrently in vivo, isolating the specific biophysical parameters that dictate emergent lamina topology has remained a major challenge. Here, we present a polymer-physics approach that explicitly resolves the spontaneous self-assembly of lamin networks under nuclear confinement. By modeling lamin dimers as semiflexible filaments with distinct interactive domains, we demonstrate that the formation of continuous, high-aspect-ratio fibers strictly requires a coordination cascade of parallel lateral alignment sites and longitudinal head-to-tail interactions between lamins. We show that the thermodynamic affinity between lamin-A and the peripheral boundary (i.e., the inner nuclear membrane and lamin B network) acts as a kinetic switch: weak surface adsorption drives network phase separation and large lamin-free gaps, whereas robust substrate binding stabilizes highly branched networks with uniform lamin distribution. Finally, uniaxial compression simulations reveal that mutations altering these molecular binding interfaces severely compromise macroscale nuclear load-bearing capacity and induce structural vulnerabilities. Collectively, our model establishes a predictive, multi-scale view that directly bridges nanoscale lamin interactions with mesoscale topological remodeling of lamina and macroscale nuclear mechanopathology.