Wang Xiaoling, Vitalis Andreas, Wyczalkowski Matthew A, Pappu Rohit V
Department of Biomedical Engineering, Washington University, St. Louis, Missouri 63130, USA.
Proteins. 2006 May 1;63(2):297-311. doi: 10.1002/prot.20761.
Studies of synthetic polyglutamine peptides in vitro have established that polyglutamine peptides aggregate via a classic nucleation and growth mechanism. Chen and colleagues [Proc Natl Acad Sci U S A 2002;99:11884-11889] have found that monomeric polyglutamine, which is a disordered statistical coil in solution, is the critical nucleus for aggregation. Therefore, nucleation of beta-sheet-rich aggregates requires an initial disorder to order transition, which is a highly unfavorable thermodynamic reaction. The questions of interest to us are as follows: What are the statistical fluctuations that drive beta-sheet formation in monomeric polyglutamine? How do these fluctuations vary with chain length? And why is this process thermodynamically unfavorable, that is, why is monomeric polyglutamine disordered? To answer these questions we use multiple molecular dynamics simulations to provide quantitative characterization of conformational ensembles for two short polyglutamine peptides. We find that the ensemble for polyglutamine is indeed disordered. However, the disorder is inherently different from that of denatured proteins and the average compactness and magnitude of conformational fluctuations increase with chain length. Most importantly, the effective concentration of sidechain primary amides around backbone units is inherently high and peptide units are solvated either by hydrogen bonds to sidechains or surrounding water molecules. Due to the multiplicity of backbone solvation modes the probability associated with any specific backbone conformation is small, resulting in a conformational entropy bottleneck which makes beta-sheet formation in monomeric polyglutamine thermodynamically unfavorable.
体外合成聚谷氨酰胺肽的研究表明，聚谷氨酰胺肽通过经典的成核和生长机制聚集。陈及其同事[《美国国家科学院院刊》2002年；99:11884 - 11889]发现，单体聚谷氨酰胺在溶液中是无序的统计卷曲结构，是聚集的关键核。因此，富含β - 折叠的聚集体的成核需要从初始无序到有序的转变，这是一个高度不利的热力学反应。我们感兴趣的问题如下：驱动单体聚谷氨酰胺中β - 折叠形成的统计涨落是什么？这些涨落如何随链长变化？以及为什么这个过程在热力学上是不利的，即为什么单体聚谷氨酰胺是无序的？为了回答这些问题，我们使用多个分子动力学模拟来对两种短聚谷氨酰胺肽的构象系综进行定量表征。我们发现聚谷氨酰胺的构象系综确实是无序的。然而，这种无序本质上不同于变性蛋白质的无序，并且平均紧密程度和构象涨落的幅度随链长增加。最重要的是，主链单元周围侧链伯酰胺的有效浓度本质上很高，肽单元通过与侧链的氢键或周围水分子溶剂化。由于主链溶剂化模式的多样性，与任何特定主链构象相关的概率很小，导致构象熵瓶颈，这使得单体聚谷氨酰胺中β - 折叠的形成在热力学上是不利的。
