SISSA , Via Bonomea 265, Trieste, Italy.
J Am Chem Soc. 2012 Feb 29;134(8):3886-94. doi: 10.1021/ja210826a. Epub 2012 Feb 16.
Starting from a disordered aggregate, we have simulated the formation of ordered amyloid-like beta structures in a system formed by 18 polyvaline chains in explicit solvent, employing molecular dynamics accelerated by bias-exchange metadynamics. We exploited 8 different collective variables to compute the free energy of hundreds of putative aggregate structures, with variable content of parallel and antiparallel β-sheets and different packing among the sheets. This allowed characterizing in detail a possible nucleation pathway for the formation of amyloid fibrils: first the system forms a relatively large ordered nucleus of antiparallel β-sheets, and then a few parallel sheets start appearing. The relevant nucleation process culminates at this point: when a sufficient number of parallel sheets is formed, the free energy starts to decrease toward a new minimum in which this structure is predominant. The complex nucleation pathway we found cannot be described within classical nucleation theory, namely employing a unique simple reaction coordinate like the total content of β-sheets.
我们从无序聚集体开始，在含有 18 条多价缬氨酸链的明胶溶剂体系中，采用偏置交换元动力学加速的分子动力学模拟了有序淀粉样 β 结构的形成。我们利用 8 种不同的集体变量计算了数百种假定的聚集体结构的自由能，这些结构具有不同的平行和反平行 β-折叠含量以及不同的片层堆积方式。这使我们能够详细描述形成淀粉样纤维的可能成核途径：首先，系统形成相对较大的反平行 β-片层有序核，然后开始出现一些平行片层。此时，相关的成核过程达到顶点：当形成足够数量的平行片层时，自由能开始向新的最小值下降，在此结构中占主导地位。我们发现的复杂成核途径不能用经典成核理论来描述，也就是说，不能只用像β-折叠总量这样的单一简单反应坐标来描述。
