10.1021/jacs.8b11698.s001 Bin Liu Bin Liu Charalampos G. Pappas Charalampos G. Pappas Ennio Zangrando Ennio Zangrando Nicola Demitri Nicola Demitri Piotr J. Chmielewski Piotr J. Chmielewski Sijbren Otto Sijbren Otto Complex Molecules That Fold Like Proteins Can Emerge Spontaneously American Chemical Society 2018 self-synthesizing macrocyclic foldamer structure drives Complex Molecules ring sizes Emerge Spontaneously interconverting molecules noncovalent interactions peptide-nucleobase subunits Single-crystal X-ray crystallography synthesis combinatorial chemistry NMR combinatorial chemistry approach design approaches complexity 2018-12-18 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Complex_Molecules_That_Fold_Like_Proteins_Can_Emerge_Spontaneously/7594235 Folding can bestow macromolecules with various properties, as evident from nature’s proteins. Until now complex folded molecules are the product either of evolution or of an elaborate process of design and synthesis. We now show that molecules that fold in a well-defined architecture of substantial complexity can emerge autonomously and selectively from a simple precursor. Specifically, we have identified a self-synthesizing macrocyclic foldamer with a complex and unprecedented secondary and tertiary structure that constructs itself highly selectively from 15 identical peptide-nucleobase subunits, using a dynamic combinatorial chemistry approach. Folding of the structure drives its synthesis in 95% yield from a mixture of interconverting molecules of different ring sizes in a one-step process. Single-crystal X-ray crystallography and NMR reveal a folding pattern based on an intricate network of noncovalent interactions involving residues spaced apart widely in the linear sequence. These results establish dynamic combinatorial chemistry as a powerful approach to developing synthetic molecules with folding motifs of a complexity that goes well beyond that accessible with current design approaches. The fact that such molecules can form autonomously implies that they may have played a role in the origin of life at earlier stages than previously thought possible.