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首页> 外文期刊>Journal of Molecular Biology >A comparative study of amyloid fibril formation by residues 15-19 of the human calcitonin hormone: a single beta-sheet model with a small hydrophobic core.
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A comparative study of amyloid fibril formation by residues 15-19 of the human calcitonin hormone: a single beta-sheet model with a small hydrophobic core.

机译：人降钙素激素15-19残基形成淀粉样蛋白原纤维的比较研究：具有小的疏水核心的单一β-折叠模型。

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摘要

Experimentally, the human calcitonin hormone (hCT) can form highly stable amyloid protofibrils. Further, a peptide consisting of hCT residues 15-19, DFNKF, was shown to create highly ordered fibrils, similar to those formed by the entire hormone sequence. However, there are limited experimental data regarding the detailed 3D arrangement of either of these fibrils. We have modeled the DFNKF protofibril, using molecular dynamics simulations. We tested the stabilities of single sheet and of various multi sheet models. Remarkably, our most ordered and stable model consists of a parallel-stranded, single beta-sheet with a relatively insignificant hydrophobic core. We investigate the chemical and physical interactions responsible for the high structural organization of this single beta-sheet amyloid fibril. We observe that the most important chemical interactions contributing to the stability of the DFNKF organization are electrostatic, specifically between the Lys and the C terminus, between the Asp and N terminus, and a hydrogen bond network between the Asn side-chains of adjacent strands. Additionally, we observe hydrophobic and aromatic pi stacking interactions. We further simulated truncated filaments, FNKF and DFNK. Our tetra-peptide mutant simulations assume models similar to the penta-peptide. Experimentally, the FNKF does not create fibrils while DFNK does, albeit short and less ordered than DFNKF. In the simulations, the FNKF system was less stable than the DFNK and DFNKF. DFNK also lost many of its original interactions becoming less organized, however, many contacts were maintained. Thus, our results emphasize the role played by specific amino acid interactions. To further study specific interactions, we have mutated the penta-peptide, simulating DANKF, DFNKA and EFNKF. Here we describe the model, its relationship to experiment and its implications to amyloid organization.
机译：实验上，人降钙素激素（hCT）可以形成高度稳定的淀粉样原纤维。此外，显示出由hCT残基15-19，DFNKF组成的肽产生高度有序的原纤维，类似于由整个激素序列形成的原纤维。但是，有关这些原纤维中任何一个的详细3D排列的实验数据有限。我们已经使用分子动力学模拟对DFNKF原纤维进行了建模。我们测试了单张纸和各种多张纸模型的稳定性。值得注意的是，我们最有序，最稳定的模型由具有相对微不足道的疏水核的平行链，单个β-折叠组成。我们调查的化学和物理相互作用，导致这种单一的β-表淀粉样蛋白原纤维的高结构组织。我们观察到，对DFNKF组织稳定性最重要的化学相互作用是静电，特别是在Lys和C末端之间，Asp和N末端之间，以及相邻链的Asn侧链之间的氢键网络。此外，我们观察到疏水性和芳香性pi堆积相互作用。我们进一步模拟了截断的细丝FNKF和DFNK。我们的四肽突变体模拟假定模型与五肽相似。实验上，FNKF不会产生原纤维，而DFNK会产生原纤维，尽管比DFNKF短且有序。在仿真中，FNKF系统不如DFNK和DFNKF稳定。 DFNK也失去了许多原始的互动，变得越来越缺乏组织性，但是仍然保持了许多联系。因此，我们的结果强调了特定氨基酸相互作用的作用。为了进一步研究特定的相互作用，我们突变了五肽，模拟了DANKF，DFNKA和EFNKF。在这里，我们描述了该模型，其与实验的关系及其对淀粉样蛋白组织的影响。

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