Proteins are folded to avoid exposure of the nonpolar groups to water because water-mediated interactions between nonpolar groups are a promising factor in the thermodynamic stabilities of proteins—which is a well-accepted view as one of the unique effects of hydrophobic interactions. This article poses a critical question for this classical view by conducting an accurate solvation free-energy calculation for a thermodynamic cycle of a protein folding using a liquid-state density functional theory. Here, the solvation-free energy for a leucine zipper formation was examined in the coiled-coil protein GCN4-p1, a typical model for hydrophobic interactions, which demonstrated that water-mediated interactions were unfavorable for the association of nonpolar groups in the native state, while the dispersion forces between them were, instead, responsible for the association. Furthermore, the present analysis well predicted the isolated helical state stabilized by pressure, which was previously observed in an experiment. We reviewed the problems in the classical concept and semiempirical presumption that the energetic cost of the hydration of nonpolar groups is a driving force of folding.

中文翻译：

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水介导的相互作用使蛋白质不稳定

蛋白质被折叠以避免非极性基团暴露于水，因为非极性基团之间的水介导的相互作用是蛋白质热力学稳定性的一个有希望的因素——这是一种广为接受的观点，是疏水相互作用的独特影响之一。本文通过使用液态密度泛函理论对蛋白质折叠的热力学循环进行准确的溶剂化自由能计算，为这一经典观点提出了一个关键问题。在这里，在卷曲螺旋蛋白 GCN4-p1 中检查了亮氨酸拉链形成的无溶剂化能量，这是疏水相互作用的典型模型，这表明水介导的相互作用不利于天然状态下非极性基团的结合，而它们之间的色散力反而是 负责协会工作。此外，本分析很好地预测了由压力稳定的孤立螺旋状态，这是之前在实验中观察到的。我们回顾了经典概念和半经验假设中的问题，即非极性基团水合的能量成本是折叠的驱动力。