Context-dependence of the contiribution of disulfide bonds to β-hairpin stability
Context-dependence of the contiribution of disulfide bonds to β-hairpin stability
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DOI：
10.1002/chem.200700845
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发表时间：
2008-01-01
影响因子：
4.3
通讯作者：
Jimenez, M. Angeles
中科院分区：
文献类型：
--
作者：
Santiveri, Clara M.;Leon, Esther;Jimenez, M. Angeles
掺入二硫键以稳定蛋白质和肽结构并不总是成功的策略。为了进一步了解二硫键对β-发夹稳定性的贡献，以先前报道的P-发夹形成肽为模板，设计了一系列含Cys的肽。这些肽在其氧化，二硫键环化肽，和还原，线性肽的构象行为，进行了研究的基础上的NMR参数：NOE，和H-1和C-13化学位移。我们发现二硫键对P-发夹稳定性的影响取决于它在P-发夹结构中的位置，当连接两个氢键面对的残基时，二硫键非常小甚至不稳定。当二硫键连接非氢键面对的残基时，我们估计它对P-发夹折叠的自由能变化的贡献约为-1.0 kcal mol（-1）。该值大于大多数β-毛发不稳定性交叉链侧链-侧链相互作用的报告值，除了一些芳香族-芳香族相互作用，特别是Trp-Trp相互作用，以及Trp和非天然甲基化Arg/Lys之间的阳离子-π相互作用。由于二硫键经常用于稳定肽构象，我们的结论可以用于肽，肽模拟物和蛋白质的设计，甚至可以扩展到其他化学交联。
Incorporation of disulfide bonds to stabilize protein and peptide structures is not always a successful strategy. To advance current knowledge on the contribution of disulfide bonds to beta-hairpin stability, a previously reported P-hairpin-forming peptide was taken as a template to design a series of Cys-containing peptides. The conformational behavior of these peptides in their oxidized, disulfide-cyclized peptides, and reduced, linear peptides, was investigated on the basis of NMR parameters: NOEs, and H-1 and C-13 chemical shifts. We found that the effect of disulfide bonds on P-hairpin stability depends on its location within the P-hairpin structure, being, very small or even destabilizing when connecting two hydrogen-bonded facing residues. When the disulfide bond is linking non-hydrogen-bonded facing residues, we estimated that its contribution to the free-energy change of P-hairpin folding is approximately -1.0 kcal mol(-1). This value is larger than those reported for most beta-hairp-instabilizing cross-strand side-chain-side-chain interactions, except for some aromatic-aromatic interactions, in particular the Trp-Trp one, and the cation-pi interaction between Trp and the non-natural methylated Arg/Lys. As disulfide bonds are frequently used to stabilize peptide conformations, our conclusions can be useful for peptide, peptidomimetic, and protein design, and may even extend to other chemical cross-links.