Crowding, Sticking, and Partial Folding of GTT WW Domain in a Small Cytoplasm Model
Crowding, Sticking, and Partial Folding of GTT WW Domain in a Small Cytoplasm Model
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DOI：
10.1021/acs.jpcb.0c02536
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发表时间：
2020-06-11
影响因子：
3.3
通讯作者：
Gruebele, M.
中科院分区：
文献类型：
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作者：
Rickard, M. M.;Zhang, Y.;Gruebele, M.
最近的实验数据表明，在细胞质中的蛋白质折叠在速度、稳定性和残存结构方面可能与体外折叠不同。在这里，我们研究了在一个小细菌细胞质模型中使用三力场对9个拷贝的模型蛋白质GTT WW结构域的全原子分子动力学(MD)模拟。MD在水溶液中已经对GTT进行了很好的研究，以供比较。我们发现，折叠的副本在25亩的S中保持折叠，而未折叠的副本在高达190亩的S中不折叠。在我们的细胞质模型中，未折叠的GTT确实存在部分折叠的中间产物，两个发夹中的一个形成了。相对于水溶液，GTT以较小的RMSD和回转半径停留在亚稳态，并且与其他大分子的表面积有较大的埋藏。特别是，GTT甚至能够与其他蛋白质形成瞬时的分子间β-折叠，从而形成一种“嵌合结构”，这可能是寡聚体β-聚集体的先驱。我们得出结论，GTT的非天然突变增强的粘连是主要原因，根据我们的结果和最近的实验，我们提出，蛋白质表面与其溶剂化环境(包括伴侣)的协同进化对于蛋白质在细胞质中的折叠和扩散是重要的。
Recent experimental data has shown that protein folding in the cytoplasm can differ from in vitro folding with respect to speed, stability, and residual structure. Here we investigate the all-atom molecular dynamics (MD) simulations of 9 copies of the model protein GTT WW domain in a small bacterial cytoplasm model using three force fields. GTT has been well-studied by MD in aqueous solution for comparison. We find that folded copies remain folded for up 25 mu s, whereas unfolded copies do not fold for up to 190 mu s. Unfolded GTT in our cytoplasm model does populate partly folded intermediates with one of the two hairpins formed. Relative to aqueous solution, GTT gets stuck in metastable states with a small RMSD and radius of gyration and extensive burial of surface area against other macromolecules. In particular, GTT is even able to form transient intermolecular beta-sheets with other proteins, resulting in a "chimeric structure" that could be a precursor to oligomeric beta-aggregates. We conclude that sticking, enhanced by the non-native mutations of GTT, is largely responsible, and we propose, on the basis of our result as well as recent experiments, that coevolution of protein surfaces with their solvation environment (including chaperones) is important for folding and diffusion of proteins in the cytoplasm.