Macromolecular crowding effects on protein-protein binding affinity and specificity
Macromolecular crowding effects on protein-protein binding affinity and specificity
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DOI：
10.1063/1.3516589
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发表时间：
2010-11-28
影响因子：
4.4
通讯作者：
Mittal, Jeetain
中科院分区：
文献类型：
--
作者：
Kim, Young C.;Best, Robert B.;Mittal, Jeetain
细胞中的大分子拥挤被认为对生物学功能有显著影响，但其影响的定量模型相对不发达。拥挤对蛋白质-蛋白质相互作用的影响特别令人感兴趣，因为它们介导细胞中的许多过程，包括较大复合物的自组装、识别和信号传导。我们使用一个残差水平的粗粒度模型来研究大分子拥挤对蛋白质-蛋白质复合物组装的影响。蛋白质之间的相互作用被处理使用一个完全可转移的能量函数，和蛋白质残基与球形拥挤的相互作用是排斥的。我们发现，两个蛋白质复合物，泛素/UIM 1和细胞色素c/细胞色素c过氧化物酶的结合自由能，适度减少拥挤剂的浓度增加。为了获得稳定效果的定量描述，我们将非球面的单个蛋白质和蛋白质复合物映射到球体上，球体的半径从拥挤排除的蛋白质体积计算。通过这种对应关系，我们发现，由于拥挤的结合自由能的变化可以定量描述的缩放粒子理论模型没有任何拟合参数。不同大小的拥挤者的混合效应--就像在真实的细胞中发现的那样--可以通过具有加和性的相同模型来预测。我们还得到了显着的结果，拥挤增加了特定的复合物在拥挤的环境中的非特异性短暂的遭遇复合物的代价的分数。这一结果，由于更大的排除体积的非特异性复合物，表明，大分子拥挤可以有微妙的功能效果超出了结合和未结合的复合物的相对稳定性。(C)2010年美国物理学会。[doi：10.1063/1.3516589]
Macromolecular crowding in cells is recognized to have a significant impact on biological function, yet quantitative models for its effects are relatively undeveloped. The influence of crowding on protein-protein interactions is of particular interest, since these mediate many processes in the cell, including the self-assembly of larger complexes, recognition, and signaling. We use a residue-level coarse-grained model to investigate the effects of macromolecular crowding on the assembly of protein-protein complexes. Interactions between the proteins are treated using a fully transferable energy function, and interactions of protein residues with the spherical crowders are repulsive. We show that the binding free energy for two protein complexes, ubiquitin/UIM1 and cytochrome c/cytochrome c peroxidase, decreases modestly as the concentration of crowding agents increases. To obtain a quantitative description of the stabilizing effect, we map the aspherical individual proteins and protein complexes onto spheres whose radii are calculated from the crowder-excluded protein volumes. With this correspondence, we find that the change in the binding free energy due to crowding can be quantitatively described by the scaled particle theory model without any fitting parameters. The effects of a mixture of different-size crowders-as would be found in a real cell-are predicted by the same model with an additivity ansatz. We also obtain the remarkable result that crowding increases the fraction of specific complexes at the expense of nonspecific transient encounter complexes in a crowded environment. This result, due to the greater excluded volume of the nonspecific complexes, demonstrates that macromolecular crowding can have subtle functional effects beyond the relative stability of bound and unbound complexes. (C) 2010 American Institute of Physics. [doi:10.1063/1.3516589]