The Differential Response of Proteins to Macromolecular Crowding
The Differential Response of Proteins to Macromolecular Crowding
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DOI：
10.1371/journal.pcbi.1005040
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发表时间：
2016-07-01
影响因子：
4.3
通讯作者：
Orozco, Modesto
中科院分区：
文献类型：
--
作者：
Candotti, Michela;Orozco, Modesto
蛋白质发挥其功能的栖息地含有高达400 g/L的大分子，其中大部分是蛋白质。这种密集环境对蛋白质行为的影响经常被忽视，或者使用合成试剂（如聚乙二醇）来解决，其模拟蛋白质拥挤的能力尚未得到证实。在这里，我们对蛋白质拥挤物对三种蛋白质（即本质无序蛋白质（ACTR）、熔融球构象（NCBD）和一重结构（IRF-3）蛋白质）的结构和动力学的影响进行了全面的原子分子动力学分析。我们发现，拥挤不稳定的本地紧凑的结构，事实上，往往防止结构崩溃。聚（乙二醇）PEG 500未能再现生理相关蛋白质拥挤的许多方面，因此表明其不适合模拟细胞内部。相反，蛋白质拥挤对蛋白质的结构和动力学的影响取决于其无序程度，并且来自两种竞争效应：排斥体积，这有利于紧凑状态，和五元相互作用，这有利于扩展构象。这样的粘性环境减慢了蛋白质的灵活性，并限制了构象景观，往往偏向生物活性构象，但阻碍生物相关的蛋白质-蛋白质接触。总的来说，这里使用的蛋白质crowders作为非特异性伴侣，调节蛋白质构象空间，从而对无序蛋白质产生相关的后果。
The habitat in which proteins exert their function contains up to 400 g/L of macromolecules, most of which are proteins. The repercussions of this dense environment on protein behavior are often overlooked or addressed using synthetic agents such as poly(ethylene glycol), whose ability to mimic protein crowders has not been demonstrated. Here we performed a comprehensive atomistic molecular dynamic analysis of the effect of protein crowders on the structure and dynamics of three proteins, namely an intrinsically disordered protein (ACTR), a molten globule conformation (NCBD), and a one-fold structure (IRF-3) protein. We found that crowding does not stabilize the native compact structure, and, in fact, often prevents structural collapse. Poly(ethylene glycol) PEG500 failed to reproduce many aspects of the physiologically-relevant protein crowders, thus indicating its unsuitability to mimic the cell interior. Instead, the impact of protein crowding on the structure and dynamics of a protein depends on its degree of disorder and results from two competing effects: the excluded volume, which favors compact states, and quinary interactions, which favor extended conformers. Such a viscous environment slows down protein flexibility and restricts the conformational landscape, often biasing it towards bioactive conformations but hindering biologically relevant protein-protein contacts. Overall, the protein crowders used here act as unspecific chaperons that modulate the protein conformational space, thus having relevant consequences for disordered proteins.