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Supramolecular Chemical Biology Modulation of Protein-Protein Interactions

Final Report Summary - SUPRACHEMBIO (Supramolecular Chemical Biology Modulation of Protein-Protein Interactions)

Supramolecular chemistry has primarily found its inspiration in biomolecules, such as proteins, DNA, lipids, and their interactions. Currently the supramolecular assembly of designed compounds can be controlled to great extent. This provides the opportunity to combine synthetic supramolecular systems with biomolecules and cells to modulate biological phenomena.[1] This ERC starting grant research project has been addressing this specific issue, to bring supramolecular chemical biology forward as a novel concept to study and modulate biology. Focus has been on two conceptual approaches regarding controlled supramolecular protein dimerization using host guest-chemistry concepts and supramolecular multivalent architectures for the assembly of proteins and recognition of cellular proteins.
Synthetic host-guest systems have been developed and applied for the controlled and reversible dimerization and immobilization of proteins. Host-guest elements based on cyclodextrins were used and appended to proteins to induce or stabilize protein heterodimerization.[2] Alternatively, cucurbituril based systems were also used to recognize specific protein elements and applied as supramolecular inducers of protein homodimerization.[3] In this way, we have generated so-called supramolecular inducers of dimerization that can act as allosteric modulators of protein dimerization and allow for example for highly efficient and reversible enzyme activation, as well as for controlled and reversible immobilization of proteins for bionanotechnological applications.
Self-assembling supramolecular architectures provide attractive scaffolds for the organized and modular display of biological ligands. Their dynamic nature allows for simple non-covalent synthesis of multivalent structures and for the introduction of multiple different functionalities. We have developed and applied two types of supramolecular architectures, based on either a columnar[4] or spherical[5] geometry. These supramolecular assemblies were shown to allow for the assembly of proteins along the supramolecular framework and for the recognition and entry of cells. The facile supramolecular synthesis of these novel materials allows for a building block approach to design and tune the optimal properties of the supramolecular materials, such as ligand density and heterovalency.
[1] Chem. Soc. Rev. 2010, 39, 2817-2826.
[2] e.g. Angew. Chem. Int. Ed. 2007, 46 1798-1802; J. Am. Chem. Soc. 2012, 134, 19199-19206.
[3] e.g. Angew. Chem. Int. Ed. 2010, 49, 895-898; Angew. Chem. 2013, 125, 2987-2991.
[4] e.g. Angew. Chem. Int. Ed. 2009, 48, 2921-2924; J. Am. Chem. Soc., 2012, 134, 8086-8089.
[5] e.g. J. Am. Chem. Soc. 2011, 133, 17063-17071.