Sequence-Specific Peptide Synthesis by an Artificial Small-Molecule Machine

Science

http://www.sciencemag.org/content/339/6116/189.full?rss=1

Bartosz Lewandowski¹,Guillaume De Bo¹,John W. Ward¹,Marcus Papmeyer¹,Sonja Kuschel¹,María J. Aldegunde²,Philipp M. E. Gramlich²,Dominik Heckmann²,Stephen M. Goldup²,Daniel M. D’Souza²,Antony E. Fernandes²,David A. Leigh¹,²,*

The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ~10¹⁸ molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.