Hernik-Magoń Agnieszka, Puławski Wojciech, Fedorczyk Bartłomiej, Tymecka Dagmara, Misicka Aleksandra, Szymczak Piotr, Dzwolak Wojciech
Department of Chemistry, Biological and Chemical Research Centre, and ‡Institute of Theoretical Physics, Faculty of Physics, University of Warsaw , Warsaw, Poland.
Biomacromolecules. 2016 Apr 11;17(4):1376-82. doi: 10.1021/acs.biomac.5b01770. Epub 2016 Mar 7.
Chain-length polydispersity is among the least understood factors governing the fibrillation propensity of homopolypeptides. For monodisperse poly-L-glutamic acid (PLGA), the tendency to form fibrils depends of the main-chain length. Long-chained PLGA, so-called (Glu)200, fibrillates more readily than short (Glu)5 fragments. Here we show that conversion of α-helical (Glu)200 into amyloid-like β-fibrils is dramatically accelerated in the presence of intrinsically disordered (Glu)5. While separately self-assembled fibrils of (Glu)200 and (Glu)5 reveal distinct morphological and infrared characteristics, accelerated fibrillation in mixed (Glu)200 and (Glu)5 leads to aggregates similar to neat (Glu)200 fibrils, even in excess of (Glu)5. According to molecular dynamics simulations and circular dichroism measurements, local events of "misfolding transfer" from (Glu)5 to (Glu)200 may play a key role in the initial stages of conformational dynamics underlying the observed phenomenon. Our results highlight chain-length polydispersity as a potent, although so-far unrecognized factor profoundly affecting the fibrillation propensity of homopolypeptides.
链长多分散性是影响同聚多肽原纤维形成倾向的诸多因素中最不为人所理解的因素之一。对于单分散的聚-L-谷氨酸（PLGA），形成原纤维的倾向取决于主链长度。长链的PLGA，即所谓的（Glu）200，比短链的（Glu）5片段更容易形成原纤维。我们在此表明，在存在内在无序的（Glu）5的情况下，α-螺旋（Glu）200向淀粉样β-原纤维的转化会显著加速。虽然（Glu）200和（Glu）5各自自组装的原纤维具有不同的形态和红外特征，但（Glu）200和（Glu）5混合时加速的原纤维化会导致形成与纯（Glu）200原纤维相似的聚集体，即使（Glu）5过量也是如此。根据分子动力学模拟和圆二色性测量，从（Glu）5到（Glu）200的“错误折叠转移”局部事件可能在观察到的现象背后的构象动力学初始阶段起关键作用。我们的结果突出了链长多分散性是一个强大的因素，尽管迄今为止尚未被认识到，但它深刻影响同聚多肽的原纤维形成倾向。
