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

Bartosz Lewandowski, Guillaume De Bo, John W. Ward, Marcus Papmeyer, Sonja Kuschel1, María J. Aldegunde, Philipp M. E. Gramlich, Dominik Heckmann, Stephen M. Goldup, Daniel M. D’Souza, Antony E. Fernandes, and David A. Leigh
Science
DOI: 10.1126/science.1229753

Chemical synthesis has advanced by an order of magnitude in the last two decades. So much so that the once groundbreaking field of natural product synthesis has become a relatively bland arena with occaisional highlights. Many synthetic chemists have turned their attention to far grander designs, passing over the mimicking of nature, and focusing their efforts on manipulating molecules ever more precisely.

Nowhere has this been demonstrated more clearly than in the development of complex molecular machines. Chemists have employed advances in synthesis to construct molecules that rotate in only one direction, walk along a track, and even change physical properties when irradiated with light. However, the field of nanotechnology has suffered from a lack of credibility in its creations: we have yet to make a molecular machine that does something useful.

This week, a report from Leigh and co-workers has taken a large step in addressing this problem, who in doing so have gone back to copying the functions of nature to inspire their designs.

Their machine mimics the function of the ribosome, taking amino acid building blocks in sequence and constructing a predefined peptide. This involes using two carefully interlocked molecules: a macrocycle with a thiolate-supporting arm and a ‘dock’ for amino acids; and a ‘track’, along which the macrocycle moves, that is functionalised at points with a defined set of amino acids. Once the machine is assembled, the macrocycle moves along the track cleaving the amino acid building blocks one at a time and docking them together in sequence. Once free of the track, the peptide can be removed from the macrocycle and isolated.

With such encouraging steps towards creating useful systems, it’s fascinating to think about what other uses this technology could be put to. The article is well worth reading to understand the chemical makeup of this machine and its function. (It’s unfortunately to complex to reproduce here.)

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