Yang, T.; Da, X.-D.; Zhang, W.-B.* Design and Biosynthesis of Topological Proteins, Acta Polym. Sin. 2020, 51 , 804-816. (Special Issue Dedicated to Professor Lina Zhang on the Occasion of Her 80th Birthday)

Abstract: Topological proteins are proteins possessing non-linear backbones and nontrivial chemical topology. Since nascent polypeptide chains are strictly linear as defined by the translational mechanism of the cellular machinery, synthesis of topological proteins remains a huge challenge. By folding into various three-dimensional shapes, proteins can gain certain control over the spatial relationship of secondary motifs, however, the diversity of the chemical topology of the backbone remains largely untapped. The discovery of natural topological proteins in the past decades have inspired the researchers to explore the design and synthesis of artificial topological proteins. Meanwhile, the progresses in supramolecular chemistry and topological polymer chemistry have brought in various strategies for the synthesis of topological molecules in general. Among them, the “assembly-reaction” synergy seems to be a generally applicable and powerful one in creating unconventional structures. With genetically encoded entangling protein motifs and genetically encoded peptide-protein reactive pairs, different topological proteins have been prepared, including cyclic proteins, star proteins, branched proteins, tadpole proteins and protein catenanes. While structures and functions are well preserved in most cases, they also exhibit considerable advantages in terms of thermal stability and resistance to chemical denaturation and proteolytic digestion. Herein, begin with the major challenges in the synthesis of topological polymers, we summarize the biosynthesis of topological proteins in nature and the recent efforts to design and construct artificial topological proteins in chemistry. We will discuss the strategies for their synthesis and characterization, as well as the potential functional benefits of topological proteins. Finally, we will present our perspective on the challenges and opportunities of this emerging field.