The nuclear lamina is widely recognized as the most crucial component in providing mechanical stability to the nucleus. However, it is still a significant challenge to model the mechanics of this multilayered protein network. We developed a constitutive model of the nuclear lamina network based on its microstructure, which accounts for the deformation phases at the dimer level, as well as the orientational arrangement and density of lamin filaments. Instead of relying on homology modeling in the previous studies, we conducted molecular simulations to predict the force-extension response of a highly accurate lamin dimer structure obtained through X-ray diffraction crystallography experimentation. Furthermore, we devised a semiflexible worm-like chain extension-force model of lamin dimer as a substitute, incorporating phases of initial stretching, uncoiling of the dimer coiled-coil, and transition of secondary structures. Subsequently, we developed a 2D network continuum model for the nuclear lamina by using our extension-force lamin dimer model and derived stress resultants. By comparing with experimentally measured lamina modulus, we found that the lamina network has sharp initial strain-hardening behavior. This also enabled us to carry out finite element simulations of the entire nucleus with an accurate microstructure-based nuclear lamina model. Finally, we conducted simulations of transendothelial transmigration of a nucleus and investigated the impact of varying network density and uncoiling constants on the critical force required for successful transmigration. The model allows us to incorporate the microstructure characteristics of the nuclear lamina into the nucleus model, thereby gaining insights into how laminopathies and mutations affect nuclear mechanics.

中文翻译：

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基于微结构的核层本构模型

核纤层被广泛认为是为细胞核提供机械稳定性的最关键的组成部分。然而，对这种多层蛋白质网络的机制进行建模仍然是一个重大挑战。我们根据核纤层网络的微观结构开发了核纤层网络的本构模型，该模型解释了二聚体水平的变形阶段以及核纤层丝的取向排列和密度。我们没有依赖先前研究中的同源建模，而是进行分子模拟来预测通过 X 射线衍射晶体学实验获得的高精度核纤层蛋白二聚体结构的力延伸响应。此外，我们设计了一种核纤层蛋白二聚体的半柔性蠕虫状链延伸力模型作为替代品，包括初始拉伸、二聚体卷曲螺旋的解卷和二级结构的转变阶段。随后，我们通过使用我们的延伸力核纤层蛋白二聚体模型和衍生的应力合成，开发了核纤层的二维网络连续体模型。通过与实验测量的层板模量进行比较，我们发现层板网络具有尖锐的初始应变硬化行为。这也使我们能够使用基于精确微观结构的核层模型对整个核进行有限元模拟。最后，我们对细胞核的跨内皮迁移进行了模拟，并研究了不同的网络密度和解卷常数对成功迁移所需的临界力的影响。该模型使我们能够将核纤层的微观结构特征纳入细胞核模型中，从而深入了解核纤层病和突变如何影响核力学。