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

TLDR

The ribosome builds proteins by joining amino acids in an order dictated by messenger RNA. We designed, synthesized, and operated 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 machine is a rotaxane with a thiolate‑bearing ring that iteratively cleaves amino acids from the strand and transfers them to a peptide‑elongation site via native chemical ligation. Using ~10^18 copies of the machine in parallel, we produced milligram quantities of a single‑sequence peptide, confirmed by tandem mass spectrometry.

Abstract

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 ~10(18) molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.