Department of Chemistry, College of Chemistry and Chemical Engineering, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen, 361005, P.R. China.
Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
Nat Commun. 2022 Mar 22;13(1):1539. doi: 10.1038/s41467-022-29210-x.
Peptide heterodimers are prevalent in nature, which are not only functional macromolecules but molecular tools for chemical and synthetic biology. Computational methods have also been developed to design heterodimers of advanced functions. However, these peptide heterodimers are usually formed through noncovalent interactions, which are prone to dissociate and subject to concentration-dependent nonspecific aggregation. Heterodimers crosslinked with interchain disulfide bonds are more stable, but it represents a formidable challenge for both the computational design of heterodimers and the manipulation of disulfide pairing for heterodimer synthesis and applications. Here, we report the design, synthesis and application of interchain disulfide-bridged peptide heterodimers with mutual orthogonality by combining computational de novo designs with a directed disulfide pairing strategy. These heterodimers can be used as not only scaffolds for generating functional molecules but chemical tools or building blocks for protein labeling and construction of crosslinking hybrids. This study thus opens the door for using this unexplored dimeric structure space for many biological applications.
肽杂二聚体在自然界中很普遍，它们不仅是功能大分子，还是化学和合成生物学的分子工具。已经开发出计算方法来设计具有先进功能的杂二聚体。然而，这些肽杂二聚体通常通过非共价相互作用形成，容易解离，并受到浓度依赖性的非特异性聚集的影响。通过链间二硫键交联的杂二聚体更稳定，但这对杂二聚体的计算设计以及用于杂二聚体合成和应用的二硫键配对操作都构成了巨大的挑战。在这里，我们通过将从头设计与定向二硫键配对策略相结合，报告了具有相互正交性的链间二硫键桥连肽杂二聚体的设计、合成和应用。这些杂二聚体不仅可以作为生成功能分子的支架，还可以作为蛋白质标记和交联杂合体构建的化学工具或构建块。因此，这项研究为将这种未被探索的二聚体结构空间应用于许多生物学应用开辟了道路。
