Bifurcated Hydrogen Bonds Stabilize Fibrils of Poly(L-glutamic) Acid
Bifurcated Hydrogen Bonds Stabilize Fibrils of Poly(L-glutamic) Acid
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DOI：
10.1021/jp102440n
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发表时间：
2010-06-24
影响因子：
3.3
通讯作者：
Dzwolak, Wojciech
中科院分区：
文献类型：
--
作者：
Fulara, Aleksandra;Dzwolak, Wojciech
模型化的原纤维形成均聚多肽为蛋白质错误折叠和淀粉样蛋白生成这些具有临床重要性的现象提供了许多有深刻见解的类比。在此我们表明，聚（L - 谷氨酸）酸的β(2)结构变体形成具有淀粉样形态的纤维，具有增强硫黄素T荧光的能力以及成核特性。β(2)纤维是在加热α - 螺旋聚（L - 谷氨酸）酸的水溶液时形成的，这导致无缓冲样品的pD（pH）显著升高，同时伴有具有异常红外特征的纤维沉淀：酰胺I'带大幅红移至1596 cm⁻¹，并且 - COOD伸缩带在1730和1719 cm⁻¹左右分裂为两个峰。我们提出，涉及分叉的肽羰基受体（>C = O）、主链的NH以及侧链的 - COOH质子供体的三中心氢键的形成可能是β(2)纤维所观察到的红外特征的基础。这种键在谷氨酸侧链周围紧密堆积的环境中提供了额外的构象限制，导致多肽的整体酸性降低。淀粉样纤维中分叉氢键的存在可能是纤维的坚固性、热力学稳定性以及其自身生长传播能力中一个被忽视的因素。
Model fibrillating homopolypeptides have been providing many insightful analogies to the clinically important phenomena of protein misfolding and amyloidogenesis. Here we show that the beta(2) structural variant of poly(L-glutamic) acid forms fibrils with an amyloid-like morphology, ability to enhance fluorescence of thioflavin T, and seeding properties. The beta(2) fibrils are formed upon heating of aqueous solutions of alpha-helical poly(L-glutamic) acid, which leads to a significant increase of pD (pH) of unbuffered samples and a concomitant precipitation of fibrils with unusual infrared traits: amide I' band being dramatically red-shifted to 1596 cm(-1), and the -COOD stretching band split into two peaks around 1730 and 1719 cm(-1). We are proposing that formation of three-center hydrogen bonds involving bifurcated peptide carbonyl acceptors (>C=O) and main chains' NH, as well as side chains' -COOH proton donors is likely to underlie the observed infrared characteristics of beta(2) fibrils. Such bonds provide additional conformational constraints in a tightly packed environment around glutamate side chains resulting in the decreased overall acidity of the polypeptide. The presence of bifurcated hydrogen bonds in amyloid fibrils may be an overlooked factor in fibrils' robustness, thermodynamic stability and the ability to propagate their own growth.