Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, Maryland 20850, United States.
J Am Chem Soc. 2011 Mar 16;133(10):3570-81. doi: 10.1021/ja109904u. Epub 2011 Feb 22.
A dicationic ferrocene derivative has previously been shown to bind cucurbit[7]uril (CB[7]) in water with ultrahigh affinity (ΔG(o) = -21 kcal/mol). Here, we describe new compounds that bind aqueous CB[7] equally well, validating our prior suggestion that they, too, would be ultrahigh affinity CB[7] guests. The present guests, which are based upon either a bicyclo[2.2.2]octane or adamantane core, have no metal atoms, so these results also confirm that the remarkably high affinities of the ferrocene-based guest need not be attributed to metal-specific interactions. Because we used the M2 method to compute the affinities of several of the new host-guest systems prior to synthesizing them, the present results also provide for the first blinded evaluation of this computational method. The blinded calculations agree reasonably well with experiment and successfully reproduce the observation that the new adamantane-based guests achieve extremely high affinities, despite the fact that they position a cationic substituent at only one electronegative portal of the CB[7] host. However, there are also significant deviations from experiment, and these lead to the correction of a procedural error and an instructive evaluation of the sensitivity of the calculations to physically reasonable variations in molecular energy parameters. The new experimental and computational results presented here bear on the physical mechanisms of molecular recognition, the accuracy of the M2 method, and the usefulness of host-guest systems as test-beds for computational methods.
先前已经有报道表明，二价铁茂衍生物在水中与瓜环（CB[7]）的结合具有超高亲和力（ΔG(o) = -21 kcal/mol）。在这里，我们描述了与 CB[7]在水中结合能力同样优异的新化合物，验证了我们之前的假设，即它们也是具有超高亲和力的 CB[7]主体。这些新的主体基于双环[2.2.2]辛烷或金刚烷核心，不含金属原子，因此这些结果也证实了基于二茂铁的客体具有极高亲和力并不一定归因于金属的特殊相互作用。由于我们在合成这些新的主客体体系之前使用 M2 方法计算了它们的亲和力，因此现在的结果也为该计算方法的首次盲法评估提供了依据。盲算结果与实验结果相当吻合，成功地再现了以下观察结果：尽管新的金刚烷基客体仅在 CB[7]主体的一个电负性入口处定位了一个阳离子取代基，但它们仍能实现极高的亲和力。然而，盲算结果与实验结果也存在显著偏差，这些偏差导致对一个程序错误的修正以及对计算结果对分子能量参数合理变化的敏感性的有益评估。这里呈现的新的实验和计算结果与分子识别的物理机制、M2 方法的准确性以及主客体体系作为计算方法的测试平台的实用性有关。
