Sağlikli ve hastalikli durumlarda nükleer laminanin yapisal ve dinamik özelliklerinin polimer temelli modellemesi

The nuclear lamina, composed of fibrous lamin proteins, forms a two-dimensional protein meshwork that preserves the structural integrity, elasticity, and morphology of the nucleus. These lamins—A/C-type and B-type—assemble into dynamic, mechanically responsive networks, much like semiflexible chains in polymer physics. In healthy nuclei, this network behaves as a random, isotropic meshwork, that can be disrupted in several diseases. An example is Progeria (HGPS), where a single point mutation in the LMNA gene (A-type lamins) results in a reduced exchange between peripheral lamins and nucleoplasmic ones. Mutated lamin A proteins (progerin) assemble into closely packed nematic phases at the nuclear periphery. These changes alter the B-type lamin network as well—enlarging mesh faces and disrupting overall organization—alongside affecting the mechanical properties and morphology of the nucleus. In other words, the structural properties of the lamina in health and disease affect 3D chromatin architecture and regulate the nucleus's ability to withstand mechanical stress. Despite these biological insights, the polymer physical mechanisms that govern lamin network formation, phase behavior, and mechanical response are largely unexplored. To address this, we present a coarse-grained molecular dynamics (MD) model that treats lamin filaments as rod-like polymers confined within the nucleus. Our model can recapitulate the lamina's nematic phase formation in disease with increasing lamin concentration in rigid nuclear confinement. Furthermore, at low inter-lamin attraction, lamins kinetically dissociate from the periphery, reminiscent of healthy nuclei. Under elastic nuclear confinement, surface adsorption of rod-like polymers alone is sufficient to control the shape of the elastic shell. This illustrates how polymer-surface interactions alone can independently influence nuclear morphology, irrespective of chromatin phase behavior. Furthermore, our results suggest that lamin adsorption to the elastic nucleus can affect the mechanical response in the short extension regime, acting as a determinant of nuclear stiffness in our model. This is unexpected, as experiments of isolated nuclei often attribute short-extension mechanics primarily to chromatin. We also find that the interplay of lamin intermolecular interactions yields diverse lamina topologies—from isotropic meshes to paracrystalline arrays— with varying face size, shape, and connectivity. Extending the model to include chromatin as a phase-separating polymeric component reveals a cooperative mechanism: self-assembled lamina can peripherally localize heterochromatin, establishing conventional nuclear architecture. Importantly, we find that lamin localization needs to precede lamin-heterochromatin attraction to encourage proper chromatin compartmentalization. Otherwise, chromatin fails to compartmentalize properly, and lamin fibers accumulate in the nuclear interior—disrupting both lamin and chromatin organization. Moreover, our analyses show that lamin-chromatin interactions are essential to generate a distinct mechanical response from the lamina when applying mechanical stress to the nucleus. This highlights the cooperative role of chromatin in lamina-mediated nuclear deformation. Introducing a meshless membrane to represent the nuclear envelope further captures dynamic nuclear deformations such as bleb formation and nuclear elongation, driven by distinct polymer-like behavior lamin fibers and chromatin networks. Together, this work frames nuclear lamina dysfunction in disease from a polymer physics perspective. Our results connect altered molecular interactions and lamina assembly to morphological and mechanical alterations of the eukaryotic nucleus in disease. It offers molecular dynamics framework to understand how altered lamin stoichiometry and phase behavior drive nuclear abnormalities in health and disease.