De novo design and directed folding of disulfide-bridged peptide heterodimers.
De novo design and directed folding of disulfide-bridged peptide heterodimers.
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二硫键肽异二聚体的从头设计和定向折叠
DOI：
10.1038/s41467-022-29210-x
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发表时间：
2022-03-22
影响因子：
16.6
通讯作者：
Wu C
中科院分区：
文献类型：
--
作者：
Yao S;Moyer A;Zheng Y;Shen Y;Meng X;Yuan C;Zhao Y;Yao H;Baker D;Wu C
肽异二聚体是自然界中普遍存在的一种功能大分子，是化学和合成生物学的分子工具。设计高级功能异二聚体的计算方法也得到了发展。然而，这些肽异二聚体通常是通过非共价相互作用形成的，它们容易游离并受到浓度依赖性非特异性聚集的影响。与二硫键交联的异源二聚体更稳定，但这对异源二聚体的计算设计和二硫键对的操纵在异源二聚体的合成和应用中是一个巨大的挑战。在这里，我们报道了结合计算从头设计和定向二硫配对策略，设计、合成和应用相互正交的链间二硫桥接肽异二聚体。这些异源二聚体不仅可以作为生成功能分子的支架，而且可以作为蛋白质标记和交联杂交种构建的化学工具或构建块。因此，这项研究为利用这种未开发的二聚体结构空间进行许多生物学应用打开了大门。肽异二聚体是自然界中普遍存在的一种功能大分子，是化学和合成生物学的分子工具。本文报道了通过多个二硫键交联的肽异二聚体的重新设计和定向折叠，可作为蛋白质正交标记和制备蛋白质杂交种的化学工具。
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. Peptide heterodimers are prevalent in nature, which are not only functional macromolecules but molecular tools for chemical and synthetic biology. Here the authors report de novo design and directed folding of peptide heterodimers crosslinked through multiple disulfide bonds, which can be explored as chemical tools for orthogonal labeling of proteins and preparing protein hybrids.
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影响因子：
64.8
作者：
Bhardwaj, Gaurav;Mulligan, Vikram Khipple;Bahl, Christopher D.;Gilmore, Jason M.;Harvey, Peta J.;Cheneval, Olivier;Buchko, Garry W.;Pulavarti, Surya V. S. R. K.;Kaas, Quentin;Eletsky, Alexander;Huang, Po-Ssu;Johnsen, William A.;Greisen, Per Jr;Rocklin, Gabriel J.;Song, Yifan;Linsky, Thomas W.;Watkins, Andrew;Rettie, Stephen A.;Xu, Xianzhong;Carter, Lauren P.;Bonneau, Richard;Olson, James M.;Coutsias, Evangelos;Correnti, Colin E.;Szyperski, Thomas;Craik, David J.;Baker, David
通讯作者：
Baker, David
影响因子：
15
作者：
Reinke, Aaron W.;Grant, Robert A.;Keating, Amy E.
通讯作者：
Keating, Amy E.
影响因子：
16.6
作者：
Guo, Ye;Sun, De-Meng;Tian, Chang-Lin
通讯作者：
Tian, Chang-Lin
影响因子：
16.6
作者：
Jang, Sangmok;Hyun, Soonsil;Yu, Jaehoon
通讯作者：
Yu, Jaehoon
影响因子：
4.1
作者：
Beld, Joris;Woycechowsky, Kenneth J.;Hilvert, Donald
通讯作者：
Hilvert, Donald