Department of Chemistry, New York University, 100 Washington Square East, NY 10013, New York, USA.
Angew Chem Int Ed Engl. 2023 Oct 9;62(41):e202303943. doi: 10.1002/anie.202303943. Epub 2023 Jun 2.
Mimics of protein secondary and tertiary structure offer rationally-designed inhibitors of biomolecular interactions. β-Sheet mimics have a storied history in bioorganic chemistry and are typically designed with synthetic or natural turn segments. We hypothesized that replacement of terminal inter-β-strand hydrogen bonds with hydrogen bond surrogates (HBS) may lead to conformationally-defined macrocyclic β-sheets without the requirement for natural or synthetic β-turns, thereby providing a minimal mimic of a protein β-sheet. To access turn-less antiparallel β-sheet mimics, we developed a facile solid phase synthesis protocol. We surveyed a dataset of protein β-sheets for naturally observed interstrand side chain interactions. This bioinformatics survey highlighted an over-abundance of aromatic-aromatic, cation-π and ionic interactions in β-sheets. In correspondence with natural β-sheets, we find that minimal HBS mimics show robust β-sheet formation when specific amino acid residue pairings are incorporated. In isolated β-sheets, aromatic interactions endow superior conformational stability over ionic or cation-π interactions. Circular dichroism and NMR spectroscopies, along with high-resolution X-ray crystallography, support our design principles.
蛋白质二级和三级结构的模拟物为生物分子相互作用提供了合理设计的抑制剂。β-折叠模拟物在生物有机化学中有悠久的历史，通常采用合成或天然的转角片段设计。我们假设用氢键取代物 (HBS) 取代末端的β-链间氢键，可能会导致构象确定的大环β-折叠，而无需天然或合成的β-转角，从而提供蛋白质β-折叠的最小模拟物。为了获得无转角的反平行β-折叠模拟物，我们开发了一种简便的固相合成方案。我们对蛋白质β-折叠中的天然观察到的链间侧链相互作用进行了数据集调查。这项生物信息学调查突出显示了β-折叠中芳香族-芳香族、阳离子-π 和离子相互作用的过度丰富。与天然β-折叠相对应的是，我们发现当特定的氨基酸残基对被结合时，最小的 HBS 模拟物显示出强大的β-折叠形成。在分离的β-折叠中，芳香族相互作用赋予了比离子或阳离子-π 相互作用更好的构象稳定性。圆二色性和 NMR 光谱学以及高分辨率 X 射线晶体学支持我们的设计原则。
