Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Nat Chem Biol. 2019 Apr;15(4):419-426. doi: 10.1038/s41589-019-0229-2. Epub 2019 Feb 11.
The chemical functionalities within biopolymers determine their physical properties and biological activities. The relationship between the side chains available to a biopolymer population and the potential functions of the resulting polymers, however, has proven difficult to study experimentally. Using seven sets of chemically diverse charged, polar, and nonpolar side chains, we performed cycles of artificial translation, in vitro selections for binding to either PCSK9 or IL-6 protein, and replication on libraries of random side chain-functionalized nucleic acid polymers. Polymer sequence convergence, bulk population target binding, affinity of individual polymers, and head-to-head competition among post-selection libraries collectively indicate that polymer libraries with nonpolar side chains outperformed libraries lacking these side chains. The presence of nonpolar groups, resembling functionality existing in proteins but missing from natural nucleic acids, thus may be strong determinants of binding activity. This factor may contribute to the apparent evolutionary advantage of proteins over their nucleic acid precursors for some molecular recognition tasks.
生物聚合物中的化学官能团决定了它们的物理性质和生物活性。然而，生物聚合物群体中可用的侧链与由此产生的聚合物的潜在功能之间的关系，已被证明难以通过实验研究来探究。我们使用了七组化学性质不同的带电、极性和非极性侧链，进行了人工翻译循环、针对 PCSK9 或 IL-6 蛋白的体外选择以及随机侧链功能化核酸聚合物文库的复制。聚合物序列收敛、总体种群目标结合、个别聚合物的亲和力以及选择后文库之间的直接竞争，共同表明非极性侧链的聚合物文库优于缺乏这些侧链的文库。非极性基团的存在类似于蛋白质中存在但天然核酸中缺失的功能，因此可能是结合活性的重要决定因素。对于某些分子识别任务，与它们的核酸前体相比，蛋白质的这种特性可能是其具有明显进化优势的原因之一。
