Thrombogenic collagen-mimetic peptides: Self-assembly of triple helix-based fibrils driven by hydrophobic interactions
Thrombogenic collagen-mimetic peptides: Self-assembly of triple helix-based fibrils driven by hydrophobic interactions
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DOI：
10.1073/pnas.0800291105
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发表时间：
2008-06-24
影响因子：
11.1
通讯作者：
Maryanoff, Bruce E.
中科院分区：
文献类型：
--
作者：
Cejas, Mabel A.;Kinnney, William A.;Maryanoff, Bruce E.
胶原蛋白是动物组织中不可或缺的结构蛋白，在细胞调节中起关键的功能作用。我们试图发现胶原蛋白模型肽（CmPs），将形成三重螺旋和自组装成超分子原纤维表现出胶原蛋白样的生物活性，而不预先组织的肽链通过共价键。通过将芳族基团置于代表性30-mer CMP（CMP）（10）的末端上来实现该挑战性目标，如32-mer Ia中的L-苯丙氨酸和L-五氟苯丙氨酸。对同源的29-mer 1a '-d'（少一个β）（作为头对尾相互作用的三重螺旋对）的计算研究产生了顺序为1a' > 1b，> 1c' > 1d '的稳定化能，支持疏水芳族基团可以驱动CMP自组装的假设。肽1a-d相对于结构性质和刺激人血小板的能力进行了比较研究。虽然每个32聚体形成稳定的三重螺旋（CID）光谱，只有1a和1b自组装成微米级的原纤维。光学显微镜图像为1a描绘了长的胶原样原纤维，而图像的Id没有。原子力显微镜形貌图像表明，1a和1b自组织成微纤维物种，而1c和1d不。肽1a和1b以类似于I型胶原的效力诱导人血小板聚集，而1c的效力低得多，1d是无活性的（EC 50效力：1a/1b >> 1c > 1d）。因此，1a和1b自发地自组装成血栓形成胶原蛋白模拟材料，因为特殊的端基提供的疏水芳香相互作用。这些发现对生物功能性CmPs的设计具有重要意义。
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-pentafluorophenylalanine in 32-mer la. 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 (CID) spectroscopy, only 1a and 1b self-assembled into micrometer-scale fibrils. Light microscopy images for 1a depicted long collagen-like fibrils, whereas images for Id did not. Atomic force microscopy topographical images indicated that 1a and 1b self-organize into microfibrillar species, whereas 1 c 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.