Qi Helena W, Nakka Priyanka, Chen Connie, Radhakrishnan Mala L
Department of Chemistry, Wellesley College, Wellesley, Massachusetts, United States of America.
PLoS One. 2014 Jun 10;9(6):e98618. doi: 10.1371/journal.pone.0098618. eCollection 2014.
Macromolecular crowding within the cell can impact both protein folding and binding. Earlier models of cellular crowding focused on the excluded volume, entropic effect of crowding agents, which generally favors compact protein states. Recently, other effects of crowding have been explored, including enthalpically-related crowder-protein interactions and changes in solvation properties. In this work, we explore the effects of macromolecular crowding on the electrostatic desolvation and solvent-screened interaction components of protein-protein binding. Our simple model enables us to focus exclusively on the electrostatic effects of water depletion on protein binding due to crowding, providing us with the ability to systematically analyze and quantify these potentially intuitive effects. We use the barnase-barstar complex as a model system and randomly placed, uncharged spheres within implicit solvent to model crowding in an aqueous environment. On average, we find that the desolvation free energy penalties incurred by partners upon binding are lowered in a crowded environment and solvent-screened interactions are amplified. At a constant crowder density (fraction of total available volume occupied by crowders), this effect generally increases as the radius of model crowders decreases, but the strength and nature of this trend can depend on the water probe radius used to generate the molecular surface in the continuum model. In general, there is huge variation in desolvation penalties as a function of the random crowder positions. Results with explicit model crowders can be qualitatively similar to those using a lowered "effective" solvent dielectric to account for crowding, although the "best" effective dielectric constant will likely depend on multiple system properties. Taken together, this work systematically demonstrates, quantifies, and analyzes qualitative intuition-based insights into the effects of water depletion due to crowding on the electrostatic component of protein binding, and it provides an initial framework for future analyses.
细胞内的大分子拥挤效应会影响蛋白质折叠和结合。早期的细胞拥挤模型聚焦于拥挤剂的排阻体积和熵效应，这通常有利于蛋白质形成紧密状态。最近，人们开始探索拥挤的其他效应，包括与焓相关的拥挤剂 - 蛋白质相互作用以及溶剂化性质的变化。在这项工作中，我们研究了大分子拥挤对蛋白质 - 蛋白质结合的静电去溶剂化和溶剂屏蔽相互作用成分的影响。我们的简单模型使我们能够专门关注由于拥挤导致的水耗尽对蛋白质结合的静电效应，从而使我们有能力系统地分析和量化这些潜在的直观效应。我们使用巴氏核酸酶 - 巴氏核酸酶抑制剂复合物作为模型系统，并在隐式溶剂中随机放置不带电的球体来模拟水环境中的拥挤情况。平均而言，我们发现结合时伙伴所产生的去溶剂化自由能惩罚在拥挤环境中会降低，并且溶剂屏蔽相互作用会增强。在拥挤剂密度恒定（拥挤剂占据的总可用体积分数）的情况下，这种效应通常会随着模型拥挤剂半径的减小而增加，但这种趋势的强度和性质可能取决于用于在连续介质模型中生成分子表面的水探针半径。一般来说，去溶剂化惩罚会随着随机拥挤剂位置的变化而有很大差异。使用明确的模型拥挤剂得到的结果在定性上可能与使用降低的“有效”溶剂介电常数来考虑拥挤情况的结果相似，尽管“最佳”有效介电常数可能取决于多种系统性质。综上所述，这项工作系统地展示、量化并分析了基于定性直觉的见解，即拥挤导致的水耗尽对蛋白质结合静电成分的影响，并为未来的分析提供了一个初步框架。
