Modelling fibrillogenesis of collagen-mimetic molecules
Modelling fibrillogenesis of collagen-mimetic molecules
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DOI：
10.1101/2020.06.08.140061
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发表时间：
2020-06
期刊：
影响因子：
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通讯作者：
Anne E. Hafner;Noemi G. Gyori;Ciaran A. Bench;Luke K. Davis;A. Šarić
中科院分区：
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作者：
Anne E. Hafner;Noemi G. Gyori;Ciaran A. Bench;Luke K. Davis;A. Šarić
生物体中自组装最有力的例子之一是胶原蛋白结构的形成。I型胶原蛋白分子是细胞外基质的重要组成部分，它们在细胞外基质中自组装成具有明确条纹图案的原纤维。这种条纹状的纤维模式在动物界中被保留下来，对于确定细胞表型、细胞粘附以及组织调节和信号传导非常重要。对决定自组装胶原纤维的这种稳健形态的物理过程的理解目前几乎完全缺失。在这里，我们开发了一个最小的粗粒度的计算模型，以确定胶原蛋白模拟分子组装的物理原理。我们发现，筛选静电相互作用可以驱动形成明确的条纹形态的胶原样细丝。原纤维模式仅由分子上的电荷分布决定，并且对蛋白质浓度、单体刚性和环境条件的变化具有鲁棒性。我们发现，原纤维模式不能很容易地预测从两个单体之间的相互作用，但多体相互作用的一个紧急结果。我们的研究结果可以帮助解决疾病和衰老中的胶原蛋白重塑问题，并指导生物技术应用中胶原蛋白支架的设计。I型胶原蛋白是哺乳动物中最丰富的蛋白质。它是细胞外基质的关键组分，在细胞外基质中，它稳健地自组装成特定条纹结构的原纤维，这对正确的胶原蛋白功能至关重要。决定这种坚固的原纤维结构的分子特征目前还没有得到很好的理解。在这里，我们开发了一个最小的粗粒度模型连接的胶原蛋白样分子的设计所产生的自组装原纤维的架构。我们发现，分子表面的带电残基模式可以驱动胶原样纤维的形成，并完全控制其结构。我们的研究结果可以帮助了解疾病中观察到的胶原蛋白结构的变化，并指导合成胶原蛋白支架的设计。
One of the most robust examples of self-assembly in living organisms is the formation of collagen architectures. Collagen type I molecules are a crucial component of the extracellular-matrix where they self-assemble into fibrils of well defined striped patterns. This striped fibrilar pattern is preserved across the animal kingdom and is important for the determination of cell phenotype, cell adhesion, and tissue regulation and signalling. The understanding of the physical processes that determine such a robust morphology of self-assembled collagen fibrils is currently almost completely missing. Here we develop a minimal coarse-grained computational model to identify the physical principles of the assembly of collagen-mimetic molecules. We find that screened electrostatic interactions can drive the formation of collagen-like filaments of well-defined striped morphologies. The fibril pattern is determined solely by the distribution of charges on the molecule and is robust to the changes in protein concentration, monomer rigidity, and environmental conditions. We show that the fibril pattern cannot be easily predicted from the interactions between two monomers, but is an emergent result of multi-body interactions. Our results can help address collagen remodelling in diseases and ageing, and guide the design of collagen scaffolds for biotechnological applications. Statement of Significance Collagen type I protein is the most abundant protein in mammals. It is a crucial component of the extracellular-matrix where it robustly self-assembles into fibrils of specific striped architectures that are crucial for the correct collagen function. The molecular features that determine such robust fibril architectures are currently not well understood. Here we develop a minimal coarse-grained model to connect the design of collagen-like molecules to the architecture of the resulting self-assembled fibrils. We find that the pattern of charged residues on the surface of molecules can drive the formation of collagen-like fibrils and fully control their architectures. Our findings can help understand changes in collagen architectures observed in diseases and guide the design of synthetic collagen scaffolds.