Tangled Tail of Mechanically Interlocked Peptides

First synthesized by chemists in the 1960s, mechanically interlocked molecules (MIMs) were created out of scientific curiosity and thought only to be academic oddities. However, naturally occurring interlocked biomolecules were subsequently discovered, highlighting the potential of the mechanical bond to serve a biological function. Interlocked structures have been identified in different classes of biomolecules; for example, catenated DNA serves to regulate DNA transcription; and the capsid of the HK97 bacteriophage consists of 72 protein macrocycles interlocked into a catenated chainmail sphere for the storage of viral DNA. The fields of molecular biology, which focuses on characterizing naturally occurring interlocked biomolecules, and supramolecular chemistry, which strives to chemically synthesize ever more complex molecular topologies, have historically run orthogonally to one another. However, as the conventional subject areas blend into synthetic biology, the benefits of a combined, interdisciplinary approach are evidenced by the bioengineering of new-to-nature mechanically interlocked peptides (MIPs). As the field evolves to attract increasingly diverse and interdisciplinary interest, we feel the time is right to provide an overview of these advances and establish a unified nomenclature. By systematically reviewing the MIPs currently found in nature, and the MIMs synthesized by chemists from peptidyl components, drawing chemical comparisons between the two we hope to bridge the gap between these fields and lay the foundations for future interdisciplinary work.