Modest Protein-Crowder Attractive Interactions Can Counteract Enhancement of Protein Association by Intermolecular Excluded Volume Interactions
Modest Protein-Crowder Attractive Interactions Can Counteract Enhancement of Protein Association by Intermolecular Excluded Volume Interactions
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DOI：
10.1021/jp200625k
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发表时间：
2011-03-24
影响因子：
3.3
通讯作者：
Mittal, Jeetain
中科院分区：
文献类型：
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作者：
Rosen, Jonathan;Kim, Young C.;Mittal, Jeetain
我们研究了球形聚集体和蛋白质残基之间的吸引相互作用对两种弱结合蛋白复合物（泛素/UIM1 和细胞色素 c/细胞色素 c 过氧化物酶）的热力学和结构的影响。使用可转移的粗粒度蛋白质结合模型在一系列吸引力强度和拥挤堆积分数上进行系统复制品交换蒙特卡罗 (REMC) 模拟。我们发现拥挤者和蛋白质残基之间的适度吸引相互作用（大约 0.2 kcal/mol）可以破坏蛋白质关联的稳定性，从而抵消排除体积相互作用的稳定作用。通过结合自由能的增加来测量，蛋白质结合的不稳定随着拥挤堆积分数的增加而增加。对于临界吸引力强度值，发现该值近似独立于拥挤堆积分数，由于吸引力引起的不稳定被排除的体积相互作用的稳定效应完全抵消。相对于无拥挤解决方案，这导致结合自由能的净零变化。此外，我们发现拥挤者和蛋白质残基之间的吸引相互作用可以有利于瞬时结合的相遇复合物，而不是处于结合状态的天然特异性复合物。我们提出了一个基于缩放粒子理论的简单理论模型，并通过平均场吸引项增强，可以半定量地解释我们的模拟结果。
We study the effects of attractive interactions between spherical crowders and protein residues on the thermodynamics and structure of two weakly binding protein complexes: ubiquitin/UIM1 and cytochrome c/cytochrome c peroxidase. Systematic replica exchange Monte Carlo (REMC) simulations are performed over a range of attraction strengths and crowder packing fractions using a transferable coarse-grained protein binding model. We find that moderate attractive interactions (approximate to 0.2 kcal/mol) between crowders and protein residues can destabilize protein association, and therefore counteract the stabilizing effect of excluded volume interactions. The destabilization of protein binding, as measured by an increase in binding free energy, increases with increasing crowder packing fraction. For a critical attraction strength value, which is found to be approximately independent of crowder packing fraction, the destabilization due to attractions is exactly canceled by the stabilization effect of excluded volume interactions. This results in a net zero change in binding free energy with respect to a crowder-free solution. Further, we find that attractive interactions between crowders and protein residues can favor transiently bound encounter complexes over the native specific complexes in the bound state. We propose a simple theoretical model based on the scaled particle theory augmented by a mean-field attraction term that can explain our simulation results semiquantitatively.