Van 't Hoff Institute for Molecular Sciences, Universiteit van Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands.
Phys Chem Chem Phys. 2011 Jun 14;13(22):10457-67. doi: 10.1039/c0cp02842h. Epub 2011 Apr 18.
Triblock copolymers consisting of a silk-based ((Gly-Ala)(3)Gly-Glu) repeat flanked by hydrophilic outer blocks self-assemble into micrometer long fibrils in response to a trigger. Since the exact mechanism of the fibril formation remains unclear, we employ a multiscale modelling approach in combination with rare event simulations to elucidate key processes. Atomistic scale simulations on the silk-based block suggest a mechanism in which a polypeptide prefolded into a β-roll structure docks to the growing end of a fibril through the formation of Glu-Glu sidechain contacts. Subsequently it can slide to the optimal position before water is expelled to form a dry interface between the fibril end and the attaching block copolymer. In addition, we find that the folded state of the silk-based block is further stabilised through interactions with its neighboring block. Templated folding may also play a role in case a partially folded polypeptide attaches. The coarse-grained simulations indicate that the attachment and subsequent sliding is mediated by the hydrophilic flanks in a size dependent manner. The hydrophilic blocks prevent random aggregation and allow growth only at the end of the fibril. Our multiscale approach may be used for other fibril-forming peptides.
由丝氨酸-丙氨酸-甘氨酸((Gly-Ala)(3)Gly-Glu)重复序列组成的三嵌段共聚物，其两侧为亲水的外层嵌段，在受到触发时会自组装成微米长的原纤维。由于原纤维形成的确切机制仍不清楚，我们采用多尺度建模方法结合稀有事件模拟来阐明关键过程。基于丝氨酸的嵌段的原子尺度模拟表明了一种机制，其中多肽预折叠成β-滚结构，通过形成谷氨酸-谷氨酸侧链接触，与原纤维的生长端对接。随后，它可以在水被排出之前滑动到最佳位置，在原纤维末端和附着的嵌段共聚物之间形成干燥界面。此外，我们发现，丝氨酸基嵌段的折叠状态通过与相邻嵌段的相互作用进一步稳定。如果部分折叠的多肽附着，模板折叠也可能起作用。粗粒化模拟表明，附着和随后的滑动是通过亲水侧翼以依赖于大小的方式介导的。亲水嵌段可防止随机聚集，并仅允许在原纤维末端生长。我们的多尺度方法可用于其他原纤维形成肽。
