A molecular tweezer for lysine and arginine
A molecular tweezer for lysine and arginine
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DOI：
10.1021/ja052806a
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发表时间：
2005-10-19
影响因子：
15
通讯作者：
Klärner, FG
中科院分区：
文献类型：
--
作者：
Fokkens, M;Schrader, T;Klärner, FG
赖氨酸和精氨酸在控制基因调控、糖蛋白靶向和囊泡转运等许多生物识别过程中起关键作用。它们还存在于负责例如细菌细胞壁生物合成、阿尔茨海默氏症肽聚集和皮肤再生的信号肽序列中。迄今为止，几乎没有一种人工受体结构对肽或蛋白质中的赖氨酸残基具有选择性和有效性。介绍了一种人工分子镊子，它对赖氨酸具有极高的亲和力（在中性磷酸盐缓冲液中K-α约为5000）。它的特点是一个富含电子的环形空腔，周围装饰着两个阴离子膦酸酯基团。通过将整个氨基酸侧链穿过空腔并随后通过形成膦酸盐-铵/胍盐桥锁定，实现对精氨酸和赖氨酸的精细选择性。这种伪轮烷样几何结构也形成于小的碱性信号肽中，其可以在缓冲水溶液中以前所未有的亲和力结合。NMR滴定，NOESY和VT实验以及ITC测量和蒙特卡罗模拟一致指向一个利用货车德瓦耳斯相互作用和大量静电贡献的构象锁的组合的静电驱动的过程。由于DMSO和乙腈与空腔内的氨基酸客体竞争，助溶剂组成的简单变化使整个络合过程可逆。
Lysine and arginine play a key role in numerous biological recognition processes controlling, inter alia, gene regulation, glycoprotein targeting and vesicle transport. They are also found in signaling peptide sequences responsible, e.g. for bacterial cell wall biosynthesis, Alzheimer peptide aggregation and skin regeneration. Almost none of all artificial receptor structures reported to date are selective and efficient for lysine residues in peptides or proteins. An artificial molecular tweezer is introduced which displays an exceptionally high affinity for lysine (K-a approximate to 5000 in neutral phosphate buffer). It features an electron-rich torus-shaped cavity adorned with two peripheral anionic phosphonate groups. Exquisite selectivity for arginine and lysine is achieved by threading the whole amino acid side chain through the cavity and subsequent locking by formation of a phosphonate-ammonium/guanidinium salt bridge. This pseudorotaxane-like geometry is also formed in small basic signaling peptides, which can be bound with unprecedented affinity in buffered aqueous solution. NMR titrations, NOESY and VT experiments as well as ITC measurements and Monte Carlo simulations unanimously point to an enthalpy-driven process utilizing a combination of van der Waals interactions and substantial electrostatic contributions for a conformational lock. Since DMSO and acetonitrile compete with the amino acid guest inside the cavity, a simple change in the cosolvent composition renders the whole complexation process reversible.