Cyclic symmetry is frequent in protein and peptide homo‐oligomers, but extremely rare within a single chain, as it is not compatible with free N‐ and C‐termini. Here we describe the computational design of mixed‐chirality peptide macrocycles with rigid structures that feature internal cyclic symmetries or improper rotational symmetries inaccessible to natural proteins. Crystal structures of three C2‐ and C3‐symmetric macrocycles, and of six diverse S2‐symmetric macrocycles, match the computationally‐designed models with backbone heavy‐atom RMSD values of 1 Å or better. Crystal structures of an S4‐symmetric macrocycle (consisting of a sequence and structure segment mirrored at each of three successive repeats) designed to bind zinc reveal a large‐scale zinc‐driven conformational change from an S4‐symmetric apo‐state to a nearly inverted S4‐symmetric holo‐state almost identical to the design model. These symmetric structures provide promising starting points for applications ranging from design of cyclic peptide based metal organic frameworks to creation of high affinity binders of symmetric protein homo‐oligomers. More generally, this work demonstrates the power of computational design for exploring symmetries and structures not found in nature, and for creating synthetic switchable systems.

中文翻译：

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具有内部对称性的混合手性肽大环化合物的计算设计

循环对称性在蛋白质和肽同源寡聚体中很常见，但在单链中极为罕见，因为它与游离的N和C末端不相容。在这里，我们描述了具有刚性结构的混合手性肽大环化合物的计算设计，这些结构具有内部循环对称性或天然蛋白质难以获得的不适当的旋转对称性。三个C2和C3对称大周期的晶体结构以及六个不同的S2对称大周期的晶体结构与计算设计的模型匹配，其主链重原子RMSD值为1或更好。旨在结合锌的S4对称大环的晶体结构（由三个连续重复的每个序列镜像的序列和结构片段组成）揭示了从S4对称脱磷态到几乎倒置的大规模锌驱动构象变化S4对称全态几乎与设计模型相同。这些对称结构为从基于环肽的金属有机框架设计到创建对称蛋白均聚物的高亲和力结合剂等应用提供了有希望的起点。更概括地说，这项工作展示了计算设计的力量，可以探索自然界中不存在的对称性和结构，并可以创建合成的可切换系统。这些对称结构为从基于环肽的金属有机框架设计到创建对称蛋白均聚物的高亲和力结合剂等应用提供了有希望的起点。更概括地说，这项工作展示了计算设计的力量，可以探索自然界中不存在的对称性和结构，并可以创建合成的可切换系统。这些对称结构为从基于环肽的金属有机框架设计到创建对称蛋白均聚物的高亲和力结合剂等应用提供了有希望的起点。更概括地说，这项工作展示了计算设计的力量，可以探索自然界中不存在的对称性和结构，并可以创建合成的可切换系统。