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首页> 外文期刊>Biophysical Chemistry: An International Journal Devoted to the Physical Chemistry of Biological Phenomena >Quantitative determination of the topological propensities of amyloidogenic peptides.
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Quantitative determination of the topological propensities of amyloidogenic peptides.

机译：淀粉样蛋白生成肽拓扑倾向的定量测定。

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One of the interesting puzzles of amyloid beta-peptide of Alzheimer's disease (Abeta) is that it appears to polymerize into amyloid fibrils in a parallel beta sheet topology, while smaller subsets of the peptide produce anti-parallel beta sheets. In order to target potential weak points of amyloid fibrils in a rational drug design effort, it would be helpful to understand the forces that drive this change. We have designed two peptides CHQKLVFFAEDYNGKDEAFFVLKQHW and CHQKLVFFAEDYNGKHQKLVFFAEDW that join the significant amyloidogenic Abeta (14-23) sequence HQKLVFFAED in parallel and anti-parallel topologies, respectively. (Here, the word parallel N-termini of the hairpins were labeled with the fluorescent dye 5-((((2-iodoacetyl)amino)ethyl)amino)naphthalene-1-sulfonic acid (IAEDANS), forming a fluorescence energy transfer donor-acceptor pair with the C-terminus tryptophan. Circular dichroism results show that the anti-parallel hairpin adopts a beta-sheet conformation, while the parallel hairpin is disordered. Fluorescent Resonance Energy Transfer (FRET) results show that the distance between the donor and the acceptor is significantly shorter in the anti-parallel topology than in the parallel topology. The fluorescence intensity of anti-parallel hairpin also displays a linear concentration dependence, indicating that the FRET observed in the anti-parallel hairpin is from intra-molecular interactions. The results thus provide a quantitative estimate of the relative topological propensities of amyloidogenic peptides. Our FRET and CD results show that beta sheets involving the essential Abeta (14-23) fragment, strongly prefer the anti-parallel topology. Moreover, we provide a quantitative estimate of the relative preference for these two topologies. Such analysis can be repeated for larger subsets of Abeta to determine quantitatively the relative degree of preference for parallel/anti-parallel topologies in given fragments of Abeta.
机译：阿尔茨海默氏病（Abeta）的淀粉样β肽有趣的难题之一是，它似乎以平行的β折叠拓扑结构聚合成淀粉样的原纤维，而肽的较小子集却产生了反平行的β折叠。为了在合理的药物设计工作中针对淀粉样蛋白原纤维的潜在弱点，了解驱动这种变化的因素将很有帮助。我们设计了两种肽CHQKLVFFAEDYNGKDEAFFVLKQHW和CHQKLVFFFFAEDYNGKHQKLVFFAEDW，它们分别以平行和反平行拓扑结构连接显着淀粉样蛋白形成的Abeta（14-23）序列HQKLVFFAED。 （在这里，发夹的平行N末端单词被荧光染料5-（（（（2-碘乙酰基氨基）乙基）氨基）萘-1-磺酸（IAEDANS）标记，形成了荧光能量转移供体-受体对与C端色氨酸-圆二色性结果表明，反平行发夹呈β-折叠构型，而平行发夹无序;荧光共振能量转移（FRET）结果表明，供体与发夹之间的距离反平行发夹中的受体明显短于平行拓扑，反平行发夹的荧光强度也显示出线性的浓度依赖性，这表明在反平行发夹中观察到的FRET来自分子内相互作用。因此，结果提供了对淀粉样蛋白生成肽的相对拓扑倾向的定量估计，我们的FRET和CD结果表明，涉及必不可少的Abeta（14-23）片段的β片层ENT，强烈希望使用反并行拓扑。此外，我们提供了对这两种拓扑的相对偏好的定量估计。可以对较大的Abeta子集重复进行此类分析，以定量确定给定Abeta片段中并行/反并行拓扑的相对优先级。

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