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Reaction Mechanisms

Tying knots in a molecular string

Metal ions act like chaperones to make complex tangles

by Ariana Remmel
September 2, 2020 | A version of this story appeared in Volume 98, Issue 34

Credit: Stuart Jantzen, Biocinematics
Copper and lutetium metal ions chaperone this molecular strand into a three-twist knot.

It’s annoyingly easy to tangle your headphones into a mess of knots, but tying even a simple knot in a molecular string is a significant challenge. Now, researchers have demonstrated for the first time how metal ions can coax a single molecular strand into two different types of knots. Their new strategy provides a pathway for making complex, bioinspired knots in the lab.

A molecular strand can form a trefoil or three-twist knot with help from copper and lutetium ions.
Credit: David Leigh/University of Manchester
Copper and lutetium ions help one molecular strand form two different knots by coordinating to Cu-binding (green) and Lu-binding (purple) motifs on the strand.

Early approaches to making molecular knots relied on the self-assembly of small building blocks that could be stitched together, creating highly symmetrical knots. But David A. Leigh, a supramolecular chemist at the University of Manchester, wanted to find a way to make more complicated knots that lack symmetry. His team designed a molecule with two types of metal binding motifs: 2,6-pyridine dicarboxamide (pdc) and 1,10-diphenylphenanthroline (dpp). By adding lutetium and copper, or lutetium alone, “we tie the strand up into different knots exactly the same way that you would with a shoelace,” Leigh says. (Nature 2020, DOI: 10.1038/s41586-020-2614-0)

To form the first type of knot, a lutetium ion coordinates three pdc sites in the strand, resulting in a trefoil knot. This symmetrical knot has been previously synthesized with other approaches. But to form the second type of knot, copper is introduced first to coordinate two dpp sites, forming a loop. When lutetium is added, it binds to the pdc sites and threads the strand ends through that loop. The strand ends are then joined by ring-closing metathesis so that the knots remain intact after the metal ions are removed.

The handedness of the copper-dpp complex helps direct the formation of the lutetium tangle much like traditional asymmetric catalysis. “We try to use the chirality of one tangle in the molecule to influence the chirality of the new tangle we were assembling,” Leigh says. This creates an asymmetric three-twist knot that is “by far the most complicated knot” ever made from a single strand, Leigh says.

The use of metal ions to guide the tangle formation is not unlike the way that biology uses chaperones to fold proteins. “We’re doing exactly the same with the artificial strand,” Leigh says. “We’re using metal ions as chaperones, which guide the folding of this string into a highly complicated, tangled structure.”

“It’s like tying a knot by hand,” says Yasutomo Segawa, an organic chemist at the Institute for Molecular Science, who was not involved in the study. Segawa says this “innovative and elegant” synthesis opens the doors for even more complex structures. “This work is the starting gun,” he says.

Leigh agrees that these two knots are only the beginning. He hopes that this new strategy can be used to synthesize the complex, asymmetric knots that have been observed in DNA and proteins in addition to inspiring new materials like knotted polymers.


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