TMAO Counteracts Urea Denaturation by Inhibiting Protein-Urea Preferential Interaction,Journal of the American Chemical Society

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TMAO Counteracts Urea Denaturation by Inhibiting Protein-Urea Preferential Interaction
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2017-12-22 , DOI: 10.1021/jacs.7b11695
Pritam Ganguly ₁ , Pablo Boserman ₂ , Nico F. A. van der Vegt ₃ , Joan-Emma Shea _{1,

2}

Affiliation

Osmolytes are small organic molecules that can modulate the stability and function of cellular proteins by altering the chemical environment of the cell. Some of these osmolytes work in conjunction, via mechanisms that are poorly understood. An example is the naturally occurring protein-protective osmolyte trimethylamine N-oxide (TMAO) that stabilizes cellular proteins in marine organisms against the detrimental denaturing effects of another naturally occurring osmolyte, urea. From a computational standpoint, our understanding of this counteraction mechanism is hampered by the fact that existing force fields fail to capture the correct balance of TMAO and urea interactions in ternary solutions. Using molecular dynamics simulations and Kirkwood-Buff theory of solutions, we have developed an optimized force field that reproduces experimental Kirkwood-Buff integrals. We show through the study of two model systems, a 15-residue polyalanine chain and the R2-fragment (273GKVQIINKKLDL284) of the Tau protein, that TMAO can counteract the denaturing effects of urea by inhibiting protein-urea preferential interaction. The extent to which counteraction can occur is seen to depend heavily on the amino acid composition of the peptide.

中文翻译：

TMAO 通过抑制蛋白质-尿素优先相互作用来抵消尿素变性

渗透物是有机小分子，可以通过改变细胞的化学环境来调节细胞蛋白质的稳定性和功能。这些渗透剂中的一些通过知之甚少的机制协同工作。一个例子是天然存在的蛋白质保护渗透剂三甲胺 N-氧化物 (TMAO)，它可以稳定海洋生物中的细胞蛋白质，抵抗另一种天然渗透剂尿素的有害变性作用。从计算的角度来看，我们对这种反作用机制的理解受到现有力场无法在三元溶液中正确平衡 TMAO 和尿素相互作用这一事实的阻碍。使用分子动力学模拟和 Kirkwood-Buff 解理论，我们开发了一个优化的力场，可以重现实验性 Kirkwood-Buff 积分。我们通过研究两个模型系统、15 个残基聚丙氨酸链和 Tau 蛋白的 R2 片段 (273GKVQIINKKLDL284) 表明，TMAO 可以通过抑制蛋白质-尿素优先相互作用来抵消尿素的变性作用。可以看到反作用的程度在很大程度上取决于肽的氨基酸组成。

更新日期：2017-12-22

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