University of Bordeaux, CBMN, UMR 5248, Institut Européen de Chimie Biologie , 2 rue Escarpit, 33607 Pessac, France.
CNRS, CBMN, UMR 5248 , 33600 Pessac, France.
J Am Chem Soc. 2016 Aug 17;138(32):10314-22. doi: 10.1021/jacs.6b05913. Epub 2016 Aug 1.
A synthetic helical aromatic oligoamide foldamer receptor with high affinity and selectivity for tartaric acid was subjected to a structure-based evolution of its sequence via mutations, additions, and deletions of monomers to produce a new receptor having high affinity and selectivity for malic acid, a guest that differs from tartaric acid by a single oxygen atom. Seven iteratively modified sequences were synthesized. Detailed structural investigations of host-guest complexes were carried out systematically to guide the design of the next generation. A first outcome was a reversal of selectivity of the receptors, with a starting preference for tartaric acid over malic acid of over 10(2) and an ending sequence showing a preference for malic acid over tartaric acid of over 10(2). Another outcome was a very strong enhancement of the affinity for malic acid, despite the fact that it has fewer recognition features for binding through polar interactions such as hydrogen bonds. Such a level of discrimination between resembling guests exemplifies the amenability of foldamers to outstanding achievements in molecular recognition. Altogether, our results demonstrate the viability of a rational receptor design approach that exploits the modularity of foldamer sequences and, in the case of aromatic amide foldamers, their amenability to structural elucidation, their relative ease of synthesis, and the predictability of their structure.
一种具有高亲和力和对酒石酸选择性的合成螺旋芳香寡肽折叠体受体，通过突变、添加和缺失单体，进行基于结构的序列进化，产生了一种对苹果酸具有高亲和力和选择性的新受体，苹果酸与酒石酸的区别仅在于一个氧原子。合成了七个迭代修饰的序列。系统地进行了详细的主体-客体配合物的结构研究，以指导下一代的设计。第一个结果是受体选择性的反转，起始时对酒石酸的选择性超过对苹果酸的 10^2，而最终序列对苹果酸的选择性超过对酒石酸的 10^2。另一个结果是尽管苹果酸通过氢键等极性相互作用结合的识别特征较少，但对苹果酸的亲和力有了很大的提高。在类似的客体之间进行这种程度的区分，体现了折叠体在分子识别方面取得优异成就的可行性。总之，我们的结果证明了一种合理的受体设计方法的可行性，该方法利用了折叠体序列的模块化，并且在芳香酰胺折叠体的情况下，利用了它们的结构阐明的易处理性、相对容易的合成和可预测性。
