Bennion Brian J, Daggett Valerie
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195-7610, USA.
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6433-8. doi: 10.1073/pnas.0308633101. Epub 2004 Apr 19.
Proteins are very sensitive to their solvent environments. Urea is a common chemical denaturant of proteins, yet some animals contain high concentrations of urea. These animals have evolved an interesting mechanism to counteract the effects of urea by using trimethylamine N-oxide (TMAO). The molecular basis for the ability of TMAO to act as a chemical chaperone remains unknown. Here, we describe molecular dynamics simulations of a small globular protein, chymotrypsin inhibitor 2, in 8 M urea and 4 M TMAO/8 M urea solutions, in addition to other control simulations, to investigate this effect at the atomic level. In 8 M urea, the protein unfolds, and urea acts in both a direct and indirect manner to achieve this effect. In contrast, introduction of 4 M TMAO counteracts the effect of urea and the protein remains well structured. TMAO makes few direct interactions with the protein. Instead, it prevents unfolding of the protein by structuring the solvent. In particular, TMAO orders the solvent and discourages it from competing with intraprotein H bonds and breaking up the hydrophobic core of the protein.
蛋白质对其溶剂环境非常敏感。尿素是一种常见的蛋白质化学变性剂，但一些动物体内含有高浓度的尿素。这些动物进化出了一种有趣的机制，通过使用氧化三甲胺（TMAO）来抵消尿素的影响。TMAO作为化学伴侣发挥作用的分子基础仍然未知。在这里，除了其他对照模拟外，我们还描述了一种小分子球状蛋白——胰凝乳蛋白酶抑制剂2在8M尿素和4M TMAO/8M尿素溶液中的分子动力学模拟，以在原子水平上研究这种效应。在8M尿素中，蛋白质展开，尿素通过直接和间接方式实现这种效应。相比之下，加入4M TMAO可抵消尿素的作用，蛋白质保持良好的结构。TMAO与蛋白质几乎没有直接相互作用。相反，它通过使溶剂结构化来防止蛋白质展开。特别是，TMAO使溶剂有序化，并抑制其与蛋白质内部氢键竞争以及破坏蛋白质的疏水核心。
