A team at Ulm University has succeeded in developing a tiny molecular system that moves autonomously along a predefined track – powered by chemical fuel and without external control of the individual steps. The work closes a research gap in the field of artificial molecular machines. In future, the principle could help to produce molecules that are difficult to obtain by conventional means. The results have now been published in Nature Chemistry.
In our bodies, tiny molecular machines are at work in every cell: so-called motor proteins such as kinesin or myosin transport substances, enable muscle movement and play a role in cell division. These proteins move along protein fibres – much as if walking on two legs. They are powered by energy supplied by the molecule ATP, also known as the energy currency of the cell.
Chemists have long been trying to replicate such movements with artificial molecular machines. “However, all previously known walkers had to be controlled externally, for example by adding chemicals, by light or by an electric field,” explains Max von Delius. In 2010, during his doctoral studies in Edinburgh, the professor at the Institute of Organic Chemistry I at Ulm University succeeded in making the world’s first molecules “walk” along a small molecular track. The current study, which he coordinated, has now achieved the step towards autonomy: “Our walker moves entirely on its own, as long as you keep topping up its fuel.”
How does the walker get moving?
The researchers use a phosphate group, consisting of one phosphorus atom and four oxygen atoms, as the walker. This group is an important biological building block and is involved in almost every metabolic process. The two tracks in the Ulm researchers’ experimental set-up are also made of natural substances: glycerol, a component of fats, with three possible binding sites for the phosphate group; and a derivative of the sugar inositol, which offers five binding sites for docking.
“For our phosphate group to take a step on these tracks, it has to break a bond to the molecular track – lift a foot, so to speak – and form a new bond at the next foothold,” says von Delius. “The challenge is that such PO bonds are extremely inert. Normally they break only extremely slowly – mathematically, it takes around 140,000 years for half of them to decompose. For our genetic material, this inertness is a good thing. But for a walker that is supposed to take several steps per hour, it’s a disaster.”
The researchers found the solution to this hurdle in a reactivity principle that is also known from RNA: when the phosphorus atom bonds with two neighbouring hydroxy groups (1,2-diols), a ring-shaped structure is formed that is under strain, “like a loaded crossbow,” says von Delius – and in this structure, one of the two bonds breaks within minutes.
Step by step – without falling off the track
A step of the walker therefore proceeds as follows: figuratively speaking, the phosphate group initially stands quite relaxed with one foot on its track. When the researchers then add a fuel – water-soluble carbodiimide (EDC) – this activates the phosphate group to dock with a second foot at the next position. This creates the strained ring-shaped compound mentioned above, in which the phosphate group is briefly bound to two neighbouring sites at the same time – until water allows one of the bonds to break. “The rear foot lifts off, the front foot stays put, and the phosphate group advances by one position without ever falling off the track completely. The next reaction cycle brings the next step.”
Four steps with chemical fuel
“Our study clearly demonstrates the effect of the fuel,” says first author Patrick Alexander Hoffmann from the Institute of Organic Chemistry. “Without fuel, over a period of weeks, 90 percent of the phosphate molecules accumulate at the outer end of the glycerol track, in the energetically most favourable position for them. With fuel, on the other hand, 64 percent are located at the less stable middle position after around two hours. The fuel drives the system into a state that it would hardly adopt on its own – an uphill walk, so to speak.” The effect was even more pronounced on the longer inositol scaffold: without fuel, the phosphate group did not move at all, even after eight weeks. With fuel, it migrated across all five possible positions – four steps in total.
If fuel is added continuously, this state is maintained for hours. The walkers then keep moving forward – just like a biological motor. “We extrapolated that one mole of walkers – about a fifth of a kilogram – collectively covers around 8.3 million kilometres per second during their escape from equilibrium,” says von Delius. “And the fuel is remarkably efficient: up to 19 out of every 100 fuel molecules consumed lead to a successful step.”
Work closes a research gap
“For the first time, the system combines three crucial properties: processivity, autonomy and kinetic asymmetry,” explains von Delius. “This means that the walker remains attached to its track, moves independently as long as fuel is available, and is driven out of its natural resting distribution by the energy input. With this demonstration, our work closes a gap in the field of molecular machines that has existed for many years.”
The reaction cycle they developed could help to produce hard-to-obtain molecules by using fuel to make them “uphill” in terms of their energy balance, explains von Delius. In the long term, the researchers also plan to make their walkers move specifically in one direction only and transport molecular cargo. Applications such as drug delivery are still a long way off. “But the pathway toward such long-term applications has now become visible.”
The study was coordinated by Professor Max von Delius from the Institute of Organic Chemistry I. The first author is Patrick Alexander Hoffmann. Suchismita Saha, Steffen Volk, Jing Sun and Andreas Englert were also involved in the experiments. The work was funded by the European Research Council (ERC) and the German Research Foundation (DFG).
Further information:
Prof. Dr. Max von Delius, Institute of Organic Chemistry, Ulm University, Email: max.vondelius(at)uni-ulm.de
Publication details:
Patrick Alexander Hoffmann, Suchismita Saha, Steffen Volk, Jing Sun, Andreas Englert, Max von Delius (2026): Autonomous migration of a phosphate group along glycerol and inositol scaffolds driven by a phosphodiester reaction cycle. Nature Chemistry. DOI: 10.1038/s41557-026-02240-4
Text: Christoph Karcher
Translation DeepL