Rational Design and Cellular Synthesis of Proteins with Unconventional Chemical Topology

Abstract

Comprehensive SummaryChemical topology refers to the three‐dimensional arrangement (i.e., connectivity and spatial relationship) of a molecule's constituent atoms and bonds. The molecular mechanism for translation defines the linear configuration of all nascent proteins. Nontrivial protein topology arises only upon post‐translational processing events and often imparts functional benefits such as enhanced stability, making topology a unique dimension for protein engineering. Utilizing the assembly‐reaction synergy, our group has developed several methods for the effective and convenient cellular synthesis of a variety of topological proteins, such as lasso proteins, protein rotaxanes, and protein catenanes. The work opens the access to new protein classes and paves the road toward illustrating the topological effects on structure‐function relationship of proteins, which lays solid foundation for exploring topological proteins’ practical application.What is the most favorite and original chemistry developed in your research group?Cellular synthesis of artificial topological proteins using genetically programmed post‐translational cascade events.How do you get into this specific field?I was trained as a polymer chemist and always dream of accomplishing full control over macromolecules’ length, sequence, stereochemistry, and topology. I got to learn about how nature uses polymer chemistry during my postdoc study at Caltech and was amazed by the delicate cellular machinery for making biopolymers. However, the rigorous template polymerization mechanism also defines the linear configuration of DNA, RNA, and protein. Inspired by my experience in supramolecular chemistry and genetically encoded click chemistry, I proposed the use of “assembly‐reaction” synergy to make nonlinear proteins. By pre‐programming information regarding assembly and reaction into the precursor protein's gene, the nascent linear protein knows what to do and undergoes a series of cascade events to transform into various chemical topologies. I enjoy this interdisciplinary approach in tackling a long‐standing challenge.How do you supervise your students?Recognize that students are different. Start from a small project and finish it. Be rigorous on science, but flexible on routines. Give them sufficient freedom to explore, yet not too much to get lost. Open to debate and cultivate critical thinking. Always ready to help. Try to be a role model by acts, not words.What is the most important personality for scientific research?Curiosity, courage, persistence, and optimism.What are your hobbies?Reading and hiking.If you have anything else to tell our readers, please feel free to do so.There is no real boundary between scientific disciplines. They are often set by our training and mindsets. It often requires tremendous efforts to break such boundaries in order to advance science.