A molecular mechanism for osmolyte-induced protein stability
A molecular mechanism for osmolyte-induced protein stability
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DOI：
10.1073/pnas.0606236103
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发表时间：
2006-09-19
影响因子：
11.1
通讯作者：
Rose, George D.
中科院分区：
文献类型：
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作者：
Street, Timothy O.;Bolen, D. Wayne;Rose, George D.
渗透剂是影响蛋白质稳定性的小型有机化合物，在生命系统中普遍存在。在平衡蛋白质折叠反应中，未折叠（U）可逆箭头天然（N），保护性渗透剂将平衡推向N，而变性渗透剂将平衡推向U。迄今为止，还没有通用的分子理论可以解释渗透剂与蛋白质相互作用从而影响蛋白质稳定性的机制。在这里，我们为这样的理论奠定了基础，从一个关键的观察开始：蛋白质主链从水转移到水/渗透剂溶液的自由能，Delta g(tr)，与渗透剂的分数极性表面积负相关。 Delta g(tr) 测量渗透剂稳定蛋白质的程度。因此，对这种相关性的直接解释意味着蛋白质主链和渗透剂极性基团之间的相互作用比与非极性基团的相应相互作用更有利。这种解释立即表明存在一种涉及渗透剂、骨干和水的通用机制。我们通过使用它构建定量溶剂化模型来测试这个想法，其中主链/溶剂相互作用能量是相互作用物极性的函数，并且实现给定相互作用的能量等效方式的数量是相互作用物表面积的函数。使用该模型，计算得出的 Delta g(tr) 值与测量值具有很强的相关性 (R = 0.99)。此外，该模型正确预测保护/变性渗透剂将优先排除/积聚在蛋白质骨架周围。总而言之，这些基于模型的结果合理化了渗透剂诱导的蛋白质稳定和变性实验研究中观察到的主要相互作用。
Osmolytes are small organic compounds that affect protein stability and are ubiquitous in living systems. In the equilibrium protein folding reaction, unfolded (U) reversible arrow native (N), protecting osmolytes push the equilibrium toward N, whereas denaturing osmolytes push the equilibrium toward U. As yet, there is no universal molecular theory that can explain the mechanism by which osmolytes interact with the protein to affect protein stability. Here, we lay the groundwork for such a theory, starting with a key observation: the transfer free energy of protein backbone from water to a water/osmolyte solution, Delta g(tr), is negatively correlated with an osmolyte's fractional polar surface area. Delta g(tr) measures the degree to which an osmolyte stabilizes a protein. Consequently, a straightforward interpretation of this correlation implies that the interaction between the protein backbone and osmolyte polar groups is more favorable than the corresponding interaction with nonpolar groups. Such an interpretation immediately suggests the existence of a universal mechanism involving osmolyte, backbone, and water. We test this idea by using it to construct a quantitative solvation model in which backbone/solvent interaction energy is a function of interactant polarity, and the number of energetically equivalent ways of realizing a given interaction is a function of interactant surface area. Using this model, calculated Delta g(tr) values show a strong correlation with measured values (R = 0.99). In addition, the model correctly predicts that protecting/denaturing osmolytes will be preferentially excluded/accumulated around the protein backbone. Taken together, these model-based results rationalize the dominant interactions observed in experimental studies of osmolyte-induced protein stabilization and denaturation.