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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Thrombogenic collagen-mimetic peptides: Self-assembly of triple helix-based fibrils driven by hydrophobic interactions
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Thrombogenic collagen-mimetic peptides: Self-assembly of triple helix-based fibrils driven by hydrophobic interactions

机译：形成血栓的胶原蛋白模拟肽：由疏水相互作用驱动的基于三螺旋的原纤维的自组装

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摘要

Collagens are integral structural proteins in animal tissues and play key functional roles in cellular modulation. We sought to discover collagen model peptides (CMPs) that would form triple helices and self-assemble into supramolecular fibrils exhibiting collagen-like biological activity without preorganizing the peptide chains by covalent linkages. This challenging objective was accomplished by placing aromatic groups on the ends of a representative 30-mer CMP, (GPO)_(10), as with L-phenylalanine and L-pentafluoropheny-lalanine in 32-mer 1a. Computational studies on homologous 29-mers 1a'-d' (one less GPO), as pairs of triple helices interacting head-to-tail, yielded stabilization energies in the order 1a' > 1b' > 1c' > 1d', supporting the hypothesis that hydrophobic aromatic groups can drive CMP self-assembly. Peptides 1a-d were studied comparatively relative to structural properties and ability to stimulate human platelets. Although each 32-mer formed stable triple helices (CD) spectroscopy, only 1a and 1b self-assembled into micrometer-scale fibrils. Light microscopy images for 1a depicted long collagen-like fibrils, whereas images for 1d did not. Atomic force microscopy topographical images indicated that 1a and 1b self-organize into microfibrillar species, whereas 1c and 1d do not. Peptides 1a and 1b induced the aggregation of human blood platelets with a potency similar to type I collagen, whereas 1c was much less effective, and 1d was inactive (EC50 potency: 1a/1b 1c > 1d). Thus, 1a and 1b spontaneously self-assemble into thrombogenic collagen-mimetic materials because of hydrophobic aromatic interactions provided by the special end-groups. These findings have important implications for the design of biofunctional CMPs.
机译：胶原蛋白是动物组织中不可或缺的结构蛋白，并在细胞调节中起关键作用。我们试图发现胶原蛋白模型肽（CMPs），它会形成三重螺旋并自组装成超分子原纤维，表现出类似于胶原蛋白的生物活性，而不会通过共价键使肽链预先组织。通过将具有代表性的30-mer CMP（GPO）_（10）末端的芳族基团与32-mer 1a中的L-苯丙氨酸和L-五氟苯丙氨酸-丙氨酸相同，可以实现这一具有挑战性的目标。对29聚体1a'-d'（少一个GPO）的计算研究，因为成对的三重螺旋从头到尾相互作用，产生的稳定能量为1a'> 1b'> 1c'> 1d'，支持疏水芳香基团可以驱动CMP自组装的假说。相对于结构特性和刺激人血小板的能力，对肽1a-d进行了比较研究。虽然每个32聚体形成稳定的三重螺旋（CD）光谱，但只有1a和1b自组装成微米级的原纤维。 1a的光学显微镜图像显示了长胶原样原纤维，而1d的图像则没有。原子力显微镜的地形图表明1a和1b自组织为微原纤维种类，而1c和1d没有。肽1a和1b诱导人血小板的聚集，其效力类似于I型胶原，而1c的效力低得多，而1d则无效（EC50效力：1a / 1b 1c> 1d）。因此，由于特殊末端基团提供的疏水性芳香族相互作用，1a和1b自发地自组装为可形成血栓的胶原蛋白模拟材料。这些发现对生物功能CMP的设计具有重要意义。

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