Entropic Stabilization of Proteins by TMAO
Entropic Stabilization of Proteins by TMAO
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DOI：
10.1021/jp207289b
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发表时间：
2011-11-17
影响因子：
3.3
通讯作者：
Thirumalai, D.
中科院分区：
文献类型：
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作者：
Cho, Samuel S.;Reddy, Govardhan;Thirumalai, D.
渗透压调节剂三甲胺N-氧化物（TMAO）在细胞中积累，以响应渗透胁迫，并增加折叠蛋白质的热力学稳定性。为了理解TMAO诱导蛋白质折叠状态稳定化的机制，我们系统地研究了TMAO对几种模型二肽（亮氨酸，L（2），丝氨酸，S（2），谷氨酰胺，Q（2），赖氨酸，K（2）和甘氨酸，G（2））的作用，以阐明残基特异性TMAO相互作用对蛋白质变性状态的溶剂暴露构象的小片段的影响。我们发现，TMAO优先与暴露的二肽骨架氢键，但一般不与非极性或极性侧链。然而，与带正电荷的Lys的相互作用显著大于与主链的相互作用。二肽G（2）是纯酰胺骨架的有用模型;通过在酰胺氮和TMAO中的氧之间形成氢键与TMAO相互作用。相比之下，TMAO从六肽G（6）中的蛋白质骨架中耗尽，这表明多肽链的长度在TMAO水溶液中是相关的。这些模拟导致的假设，TMAO诱导的蛋白质和肽的稳定是从蛋白质表面提供的分子内相互作用比TMAO和骨架之间的溶质消耗的结果。为了验证我们的假设，我们进行了TMAO对本质无序A β（16-22）（KLVFFAE）单体的作用的额外模拟。在不存在TMAO的情况下，A β（16-22）是无序的无规卷曲。而在TMAO水溶液中，A β（16-22）单体样品构象致密.在高TMAO浓度下观察到从无规卷曲到α-螺旋二级结构的过渡。卷曲到α-螺旋的转变是高度协同的，特别是考虑到A β中的残基数量较少（16-22）。我们的工作突出了TMAO对长多肽链的作用与蛋白质在拥挤环境中因排除体积相互作用而熵稳定之间的潜在相似性。从这个意义上说，化学伴侣TMAO是一种纳米颗粒。
The osmolyte trimethylamine N-oxide (TMAO) accumulates in the cell in response to osmotic stress and increases the thermodynamic stability of folded proteins. To understand the mechanism of TMAO induced stabilization of folded protein states, we systematically investigated the action of TMAO on several model dipeptides (leucine, L(2), serine, S(2), glutamine, Q(2), lysine, K(2), and glycine, G(2)) in order to elucidate the effect of residue-specific TMAO interactions on small fragments of solvent-exposed conformations of the denatured states of proteins. We find that TMAO preferentially hydrogen bonds with the exposed dipeptide backbone but generally not with nonpolar or polar side chains. However, interactions with the positively charged Lys are substantially greater than with the backbone. The dipeptide G(2) is a useful model of the pure amide backbone; interacts with TMAO by forming a hydrogen bond between the amide nitrogen and the oxygen in TMAO. In contrast, TMAO is depleted from the protein backbone in the hexapeptide G(6), which shows that the length of the polypeptide chain is relevant in aqueous TMAO solutions. These simulations lead to the hypothesis that TMAO-induced stabilization of proteins and peptides is a consequence of depletion of the solute from the protein surface provided intramolecular interactions are more favorable than those between TMAO and the backbone. To test our hypothesis, we performed additional simulations of the action of TMAO on an intrinsically disordered A beta(16-22) (KLVFFAE) monomer. In the absence of TMAO, A beta(16-22) is a disordered random coil. However, in aqueous TMAO solution, A beta(16-22) monomer samples compact conformations. A transition from random coil to alpha-helical secondary structure is observed at high TMAO concentrations. The coil to alpha-helix transition is highly cooperative especially considering the small number of residues in A beta(16-22). Our work highlights the potential similarities between the action of TMAO on long polypeptide chains and entropic stabilization of proteins in a crowded environment due to excluded volume interactions. In this sense, the chemical chaperone TMAO is a nanocrowding particle.