Complex Molecules That Fold Like Proteins Can Emerge Spontaneously
Bin Liu†, Charalampos G. Pappas†, Ennio Zangrando*‡, Nicola Demitri∥ , Piotr J. Chmielewski*§, and Sijbren Otto*†
† Centre for Systems Chemistry, Stratingh Institute, Nijenborgh 4, 9747 AG Groningen, The Netherlands
‡ Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127 Trieste, Italy
∥ Elettra−Sincrotrone Trieste, S.S. 14 Km 163.5 in Area Science Park, 34149 Basovizza, Trieste, Italy
§ Department of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50383 Wrocław, Poland
J. Am. Chem. Soc., Article ASAP
DOI: 10.1021/jacs.8b11698
Publication Date (Web): December 18, 2018
Copyright © 2018 American Chemical Society
*ezangrando@units.it, *piotr.chmielewski@chem.uni.wroc.pl, *s.otto@rug.nl
ACS Editors' Choice - This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.
Abstract
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.
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