Department of Chemistry, Texas A & M University, College Station, TX, 77842, USA.
Nat Commun. 2024 May 17;15(1):4217. doi: 10.1038/s41467-024-48323-z.
Helix mimicry provides probes to perturb protein-protein interactions (PPIs). Helical conformations can be stabilized by joining side chains of non-terminal residues (stapling) or via capping fragments. Nature exclusively uses capping, but synthetic helical mimics are heavily biased towards stapling. This study comprises: (i) creation of a searchable database of unique helical N-caps (ASX motifs, a protein structural motif with two intramolecular hydrogen-bonds between aspartic acid/asparagine and following residues); (ii) testing trends observed in this database using linear peptides comprising only canonical L-amino acids; and, (iii) novel synthetic N-caps for helical interface mimicry. Here we show many natural ASX motifs comprise hydrophobic triangles, validate their effect in linear peptides, and further develop a biomimetic of them, Bicyclic ASX Motif Mimics (BAMMs). BAMMs are powerful helix inducing motifs. They are synthetically accessible, and potentially useful to a broad section of the community studying disruption of PPIs using secondary structure mimics.
螺旋模拟物可提供用于干扰蛋白质-蛋白质相互作用（PPIs）的探针。可以通过连接非末端残基的侧链（订书钉）或通过加帽片段来稳定螺旋构象。自然界仅使用加帽，但是合成的螺旋模拟物则严重偏向订书钉。本研究包括：（i）创建可搜索的独特螺旋 N-帽（ASX 基序，一种具有两个分子内氢键的蛋白质结构基序，在天冬氨酸/天冬酰胺和随后的残基之间）数据库；（ii）使用仅包含典型 L-氨基酸的线性肽测试该数据库中观察到的趋势；以及（iii）用于螺旋界面模拟的新型合成 N-帽。在这里，我们展示了许多天然 ASX 基序包含疏水三角形，验证了它们在线性肽中的作用，并进一步开发了它们的生物模拟物，双环 ASX 基序模拟物（BAMMs）。BAMMs 是强大的螺旋诱导基序。它们具有合成可及性，并且对于使用二级结构模拟物研究破坏蛋白质-蛋白质相互作用的广大社区可能是有用的。
