Peptides synthesized from non‐canonical amino acids can adopt exotic folds inaccessible to natural proteins. Unlike proteins, small peptide macrocycles have conformation spaces that can be explored exhaustively. However, only larger macrocycles can access more complex folds potentially compatible with new functions. Here, we render larger macrocycles computationally tractable by exploring internally‐symmetric macrocycle conformations and sequences. This allowed us to design, synthesize, and solve structures of ten new symmetric macrocycles, with sub‐Ångstrom precision in most cases. Our most complex design acts as a zinc‐dependent conformational switch. We anticipate that the symmetric design methods presented here will be broadly useful for designing new synthetic peptide macrocycles with exotic folds and functions. https://doi.org/10.1002/pro.3974

由非规范氨基酸合成的肽可以采用天然蛋白质无法接近的异源折叠。与蛋白质不同，小肽大环具有构象空间，可以对其进行详尽地研究。但是，只有较大的宏周期才能访问可能与新功能兼容的更复杂的折叠。在这里，我们通过探索内部对称的大环构象和序列，使较大的大环在计算上易于处理。这使我们能够设计，合成和求解10个新的对称大环的结构，在大多数情况下，其精确度均低于埃。我们最复杂的设计充当锌依赖性构象开关。我们预计，此处介绍的对称设计方法将广泛用于设计具有异乎寻常的折叠和功能的新型合成肽大环化合物。https://doi.org/10.1002/pro。