Attachment of amino acids to hydrophobic organic molecules allows amino acids to self-assemble to form rare, handed-handed knot structures, circumventing the need for external templates or chiral resolution. This approach provides chiral and mechanically bound molecules in one step, opening new possibilities for molecular recognition, sensing, and asymmetric catalysis.

Generating large molecules entangled in the form of a single mirror image is a long-standing challenge in chemistry. Chirality underpins everything from drug activity to biological recognition, but as molecular structures become more complex, chirality becomes increasingly difficult to control. This is especially true for mechanically linked molecules such as catenanes, knots, and links that are joined by topology rather than covalent bonds.

Solomon links are one of the most complex examples. It consists of two doubly linked rings with four points of intersection and is chiral in nature due to the way the chains intersect. Few synthetic routes to these structures exist, but they typically rely on pre-engineered templates with limited control over handedness and function.

Now, the team led by Yong Kui and Kankyo-dong At Shanghai Jiao Tong University, China anthony davis and colleagues from the University of Bristol, UK, have demonstrated a biology-inspired strategy that uses amino acids to program tetraphenylethylene molecules to spontaneously form chiral Solomon bonds.

The researchers synthesized a molecular building block consisting of a hard aromatic core flanked by amino acids with pyridyl groups that bind zinc ions. When mixed with zinc salts, the components self-assemble to form Solomon bonds, but only if the amino acid residues share the same chirality. A network of hydrogen bonds between amino acids precisely aligns the molecular chains, determines which chains pass above or below another at critical points, and fixes the crossings necessary to generate the knot topology. Metal adjustments then close the ring and mechanically lock the structure in place. In contrast, achiral components or mixtures of left-handed and right-handed amino acids form simple, unentangled coordination polymers. “It is interesting to see how different structures can be obtained by adjusting the enantiopurity of the ligand used.” jamie lewisfrom the University of Birmingham, UK, and was not involved in this work.

X-ray crystallography confirmed the formation of a doubly entangled topology and revealed multiple layers of chirality from the stereogenic center of the amino acid to the topology of the entire molecule. By changing the amino acid side chains, the researchers can tune the size and chemical environment of the cavity that forms at the center of the Solomon link, which in turn affects its function. This link binds selectively to short peptides and can distinguish between enantiomers. When incorporated into polymer membranes, biologically relevant targets such as the inflammatory biomarker interleukin-6 can also be detected at nanomolar concentrations.

The researchers write that this amino acid-driven approach provides a simple one-step route to complex, chirally linked molecules. “It may not be easy to generalize this approach to other types of mechanically linked molecules, but there is no inherent reason why this would not be successful,” Lewis says. “A detailed understanding of the interactions between fragments that enable the transfer of chiral information is important for designing alternative systems using this approach.”