Oligorotaxanes, artificial molecular machines capable of exceeding the performance of natural proteins

Researchers at the NANOCHEM laboratory (MolSys Research Unit) of the University of Liege have studied molecules synthesized by Sir Fraser Stoddart's group, Nobel Prize winner in Chemistry 2016 and professor at Northwestern University. The results obtained during this research and published in Nature Nanotechnology (1) open up new paths in the use of molecular machines, these synthetic molecules that carry out controlled motion on demand.

It was back in 2016 that chemists Jean-Pierre Sauvage, Sir J. Fraser Stoddart and Ben L. Feringa, received the Nobel Prize in Chemistry for their work on the design and synthesis of molecular machines*, synthetic molecules of nanometer size that can move on demand, resulting in mechanical work. While the first developments were "limited" to the formation of two interlocked rings like links in a chain, the recent developments now make it possible to synthesize much more complex molecules and to make these molecules do perfectly controlled directional movements allowing them to carry out well-defined tasks, such as transporting objects like robotic arms do.

For the past fifteen years or so, chemists have also been designing molecules capable of folding to form well-defined three-dimensional architectures, called « foldamers », which mimic the properties of natural proteins. Much of the research focus on the effectiveness of the synthesis of these molecules. « Molecular folding is a ubiquitous process that nature uses to control the conformation of its molecular machines in order to perform chemical and mechanical tasks such as muscle contraction or cellular transport," explains Professor Anne-Sophie Duwez , director of the NANOCHEM Laboratory (Nanochemistry and Molecular Systems, MolSys Research Unit), currently the only Lab in the world able to perform custom force measurements on small synthetic molecules.

Mechanically linked molecules, such as rotaxanes (a ring threaded around an axis) and catenanes (two interlocked rings), are prototypes of molecular machines that allow the controlled movement and positioning of their components. It is by combining the elegant complexity of these two families of molecules (folded molecules and mechanically linked molecules) that the researchers at Northwestern University succeeded in synthesizing oligorotaxanes, molecules in which a molecular axis folds its way through a series of rings, in a serpentine-like fashion (Figure 1).

As part of this research, ULiège researchers and Damien Sluysmans - PhD student and first author of the paper - in particular"pulled" on these synthetic oligorotaxanes using an atomic force microscope to force them to unfold by breaking the interactions that kept the structure folded (Figure 2). They were able to see that the molecules resisted unfolding and were able to produce an intense force to remake the interactions and thus refold against the applied external force. The force exerted by these synthetic molecules to refold is much greater than the one that the equivalent natural biological molecules are able to produce.

These results, published , show that synthetic oligorotaxanes have the potential to outperform natural folding proteins.  In order to appreciate the technological potential of these results, and of synthetic molecular machines in general, it is enough to realize that natural molecular machines are at the heart of all important biological processes of living beings.

Although the prospects for the use of molecular machines are important, since these molecules could be used for the development of high-performance artificial muscles or pistons, for bringing drugs close to a cancerous tumour, or for storing and processing data on a single molecule level for the field of computing, their practical applications are a long way off. The 2016 Nobel Committee concluded its report by writing that "we are at the dawn of a new industrial revolution of the 21st century, and the future will show us how molecular machinery can become an integral part of our lives. The advances made have also led to the first steps towards creating truly programmable machines, and it can be envisaged that molecular robotics will be one of the next major scientific areas.". Anne-Sophie Duwez to conclude, « The Nobel Prize for molecular machines is a tremendous reward for inspirational basic science and scientific creativity. »

To better understand

Molecular machines are, as their name suggests, machines made of assemblies of molecular components capable of using a source of energy (light, thermal or chemical) to transform it into mechanical energy, such as the engine of a car that transforms the energy provided by fuel into mechanical energy that will make turn the wheels of the vehicle. It is thanks to these machines that living beings "function" in a global way.  These are the machines that allow our muscles to convert the chemical energy contained in our food into mechanical force. By stretching and contracting, molecular machines allow the movement of muscles.

Scientific references

(1) D. Sluysmans, S. Hubert, C. J. Bruns, Zhixue Zhu, J. F. Stoddart and A.-S. Duwez, Synthetic oligorotaxanes exert high forces when folding under mechnical load , Nature Nanotechnology , 2017.

D. Sluysmans, F. Devaux, C. J. Bruns, J. F. Stoddart, A.-S. Duwez, Proc. Natl. Acad. Sci. 2017, in press (DOI:10.1073/pnas.1712790115).

Anne-Sophie Duwez obtained her PhD in Chemistry in 1997 at the University of Namur. She then joined the Université catholique de Louvain as a FNRS postdoctoral researcher. From 2002 to 2003, she was visiting scientist at the Max Planck Institute in Mainz, Germany. She then returned to UCL to develop single molecule force spectroscopy by AFM. In 2006, she was appointed associate professor at ULiège and obtained an incentive grant for scientific research from the FNRS to create a new laboratory for advanced AFM techniques. She is currently professor in the Department of Chemistry. Her research focuses on developing AFM techniques for manipulating individual molecules. Her group is currently the only one in the world able to perform custom force measurements on small synthetic molecules.