Nature Commun. 3, 1093 (2012)

Encapsulating molecules within synthetic cages offers the potential to tailor the surrounding environment for chemical reactions in a manner similar to that used by enzymes. Small molecules have been enclosed inside a variety of hollow structures. These cages are typically formed by coordinating organic ligands around metal centres or using hydrogen bonding to hold together supramolecular structures. The interior of these synthetic structures can direct unusual regioselective or stereoselective reactions or speed up reactions in dilute solutions; however, due to their large size, proteins have resisted attempts to confine them inside discrete synthetic cages — until now.

Credit: © 2012 NPG

To crack this problem, a team led by Makoto Fujita at The University of Tokyo and Koichi Kato at Nagoya City University covalently tethered a protein (ubiquitin) to an organic bidentate ligand containing two pyridine rings. The addition of Pd(II) along with more ligand (this time without a protein attached) resulted in a hollow spherical framework self-assembling around ubiquitin (pictured). The framework skeleton is made from 12 Pd(II) atoms bridged by 24 ligands, with each Pd atom bound to 4 pyridine groups. The internal diameter of the sphere (up to 7.3 nm) could be altered by tailoring the size of the organic bridge. The cavity was only large enough, however, to accommodate one ubiquitin molecule, preventing the inclusion of more than one protein-bound ligand in each spherical frame. Diffusion and ultrafiltration experiments proved that the protein was bound to the spherical frame and X-ray crystallography confirmed that it was located inside the cage. NMR spectra showed that ubiquitin remained in its three-dimensional fully folded structure while inside the sphere, indicating that proteins encapsulated in synthetic cages might retain properties related to their tertiary structure.

Constructing a cage around a protein is only the first step towards harnessing the unique chemistry these systems can offer. The team explain that their ultimate goal is to match the conformational control that coordination cages offer to the functional control that proteins and enzymes provide.