Proteins can undergo kinetic/thermodynamic partitioning between folding and aggregation. Proper protein folding and thermodynamic stability are crucial for aggregation inhibition. Thus, proteinfolding principles have been widely believed to consistently underlie aggregation as a consequence of conformational change. However, this prevailing view appears to be challenged by the ubiquitous phenomena that the intrinsic and extrinsic factors including cellular macromolecules can prevent aggregation, independently of (even with sacrificing) protein folding rate and stability. This conundrum can be definitely resolved by 'a simple principle' based on a rigorous distinction between protein folding and aggregation: aggregation can be controlled by affecting the intermolecular interactions for aggregation, independently of the intramolecular interactions for protein folding. Aggregation is beyond protein folding. A unifying model that can conceptually reconcile and underlie the seemingly contradictory observations is described here. This simple principle highlights, in particular, the importance of intermolecular repulsive forces against aggregation, the magnitude of which can be correlated with the size and surface properties of molecules. The intermolecular repulsive forces generated by the common intrinsic properties of cellular macromolecules including chaperones, such as their large excluded volume and surface charges, can play a key role in preventing the aggregation of their physically connected polypeptides, thus underlying the generic intrinsic chaperone activity of soluble cellular macromolecules. Such intermolecular repulsive forces of bulky cellular macromolecules, distinct from protein conformational change and attractive interactions, could be the puzzle pieces for properly understanding the combined cellular protein folding and aggregation including how proteins can overcome their metastability to amyloid fibrils in vivo.

中文翻译：

---

了解组合的细胞蛋白折叠和聚集的简单原理。

蛋白质可以在折叠和聚集之间进行动力学/热力学分配。正确的蛋白质折叠和热力学稳定性对于抑制聚集至关重要。因此，人们普遍认为蛋白质折叠原理作为构象变化的结果始终是聚合的基础。但是，这种普遍的观点似乎受到普遍现象的挑战，即包括细胞大分子在内的内在因素和外在因素都可以阻止聚集，而与蛋白质折叠速率和稳定性无关（即使牺牲了）。这个难题可以通过基于蛋白质折叠和聚集之间严格区别的“简单原理”来解决：聚集可以通过影响聚集之间的分子间相互作用来控制，独立于分子内相互作用的蛋白质折叠。聚集不只是蛋白质折叠。这里描述了一个可以在概念上协调和支持看似矛盾的观察结果的统一模型。这个简单的原理特别强调了分子间排斥力对聚集的重要性，其大小可以与分子的大小和表面性质相关。由分子大分子（包括伴侣蛋白）的共同固有特性（例如其大体积的排阻体积和表面电荷）产生的分子间排斥力在阻止其物理连接多肽的聚集中起着关键作用，从而成为可溶性分子的通用固有伴侣蛋白活性的基础。细胞大分子。