Behavior of Water Near Multimodal Chromatography Ligands and Its Consequences for Modulating Protein–Ligand Interactions
Behavior of Water Near Multimodal Chromatography Ligands and Its Consequences for Modulating Protein–Ligand Interactions
复制标题
水在多模式色谱配体附近的行为及其对调节蛋白质与配体相互作用的影响
DOI：
10.1021/acs.jpcb.1c01549
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Cramer, Steven M.
中科院分区：
文献类型：
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作者：
Bilodeau, Camille L.;Lau, Edmond Y.;Roush, David J.;Snyder, Mark A.;Cramer, Steven M.
多峰层析是一种使用含有多种相互作用模式的配体来纯化蛋白质的有效方法。最近的研究表明，多峰色谱分离的选择性是配体结构和几何构型的函数。在这里，我们进行了分子动力学模拟，以探索配体结构和几何结构如何影响配体-水相互作用，以及这些溶液中的差异如何影响蛋白质-配体相互作用的性质。我们的研究集中在三个层析配体：Capto MMC，Nuvia cPrime和Prototype 4，Nuvia cPrime的结构变体。首先，通过三个指标来量化每个配体的溶剂化特征：平均水密度、波动和停留时间。然后，我们探索了当配体结合到蛋白质表面时，溶剂化是如何被扰动的，并发现苯环去湿的概率遵循以下顺序：Capto MMC>；Prototype 4>；Nuvia cPrime。为了探索这些去湿过程中的差异如何影响蛋白质-配体的相互作用，我们计算了每个配体与蛋白质表面不同类型残基结合的概率，发现与疏水残基结合的概率与去湿行为遵循相同的顺序。这项研究阐明了润湿和去湿在调节蛋白质-配体相互作用中所起的作用。
Multimodal chromatography is a powerful approach for purifying proteins that uses ligands containing multiple modes of interaction. Recent studies have shown that selectivity in multimodal chromatographic separations is a function of the ligand structure and geometry. Here, we performed molecular dynamics simulations to explore how the ligand structure and geometry affect ligand–water interactions and how these differences in solution affect the nature of protein–ligand interactions. Our investigation focused on three chromatography ligands: Capto MMC, Nuvia cPrime, and Prototype 4, a structural variant of Nuvia cPrime. First, the solvation characteristics of each ligand were quantified via three metrics: average water density, fluctuations, and residence time. We then explored how solvation was perturbed when the ligand was bound to the protein surface and found that the probability of the phenyl ring dewetting followed the order: Capto MMC > Prototype 4 > Nuvia cPrime. To explore how these differences in dewetting affect protein–ligand interactions, we calculated the probability of each ligand binding to different types of residues on the protein surface and found that the probability of binding to a hydrophobic residue followed the same order as the dewetting behavior. This study illustrates the role that wetting and dewetting play in modulating protein–ligand interactions.