Nucleic acid aptamers selected through systematic evolution of ligands by exponential enrichment (SELEX) fold into exquisite globular structures in complex with protein targets with diverse translational applications. Varying the chemistry of nucleotides allows evolution of nonnatural nucleic acids, but the extent to which exotic chemistries can be integrated into a SELEX selection to evolve nonnatural macromolecular binding interfaces is unclear. Here, we report the identification of a cubane-modified aptamer (cubamer) against the malaria biomarker Plasmodium vivax lactate dehydrogenase (PvLDH). The crystal structure of the complex reveals an unprecedented binding mechanism involving a multicubane cluster within a hydrophobic pocket. The binding interaction is further stabilized through hydrogen bonding via cubyl hydrogens, previously unobserved in macromolecular binding interfaces. This binding mechanism allows discriminatory recognition of P. vivax over Plasmodium falciparum lactate dehydrogenase, thereby distinguishing these highly conserved malaria biomarkers for diagnostic applications. Together, our data demonstrate that SELEX can be used to evolve exotic nucleic acids bearing chemical functional groups which enable remarkable binding mechanisms which have never been observed in biology. Extending to other exotic chemistries will open a myriad of possibilities for functional nucleic acids.

通过配体通过指数富集（SELEX）进行系统进化而选择的核酸适体，可以折叠成精致的球状结构，并与具有多种翻译应用的蛋白质靶标复合。改变核苷酸的化学性质允许非天然核酸的进化，但是尚不清楚外来化学物质可以整合到SELEX选择中以进化非天然大分子结合界面的程度。在这里，我们报告针对疟疾生物标志间日疟原虫的古巴修饰的适体（古巴）的鉴定。乳酸脱氢酶（PvLDH）。该复合物的晶体结构揭示了前所未有的结合机制，该机制涉及疏水口袋内的多古巴簇。结合相互作用通过以前在大分子结合界面中未观察到的通过氢苄基的氢键进一步稳定。这种结合机制允许的歧视性识别间日疟原虫在疟原虫乳酸脱氢酶，从而区分出这些高度保守的疟疾生物标志物以用于诊断应用。总之，我们的数据表明SELEX可用于进化带有化学官能团的外来核酸，这些核酸可实现在生物学中从未发现过的显着结合机制。扩展到其他外来化学将为功能性核酸带来无数的可能性。