Transducing chemical energy through catalysis

Transducing chemical energy through catalysis by an artificial molecular motor,’ Peng-Lai Wang, Stefan Borsley, Martin J. Power, Alessandro Cavasso, Nicolas Giuseppone & David A. Leigh, Nature, 637, 594–600 (2025) . Full Article.


Video: The transduction of chemical energy into mechanical work through catalysis by an artificial molecular motor. Video credit: Dr. Anna Tanczos, SciComm Studios.

It seems counter-intuitive that the act of catalysis—simply the acceleration of a chemical reaction—somehow enables work to be done by the catalyst through the transduction of chemical energy from the reaction it accelerates. Yet this is how all of biology is powered.[1,2] Almost all biomolecular motors are catalysts.[3] They transduce energy from the reaction they catalyse—generally ATP to ADP—to power the diverse array of tasks required by the cell. Evolution renders motor proteins too structurally complex to provide a straightforward answer as to how the action of catalysis enables the energy released from a chemical reaction to be transduced by the catalyst. Now, in Nature 637, 594–600 (2025),[4] the Leigh and Giuseppone groups explain how this happens. They demonstrate the transduction of chemical energy by a synthetic catalyst to generate force and perform mechanical work. The simplicity of the molecular catalyst reveals the fundamental principles behind how the process occurs. The findings add to the understanding of how biology is powered by chemical energy and provide a blueprint for how to design artificial catalysis-driven molecular nanotechnology.[5]

Gel contraction by an artificial catalysis-driven molecular motor

Cells display a range of mechanical activities enabled by the cytoskeleton, a viscoelastic hydrogel manipulated by motor proteins powered through catalysis.[1] The study by the Manchester and Strasbourg groups demonstrates the powered contraction and powered re-expansion of a hydrogel driven by the directional rotation of artificial organocatalytic molecular motors incorporated within the polymeric framework of the gel. The motor-molecules, introduced by the Leigh group in 2022,[6] generate force by the action of catalysis biasing the kinetics of ground-state conformational changes, the same type of catalysis-driven information ratchet mechanism as biological motor-molecules.[3] Continuous 360° rotation (either clockwise or anti-clockwise, depending on the chirality of the fuelling system) of the rotor about the stator of the motor-molecules twists the polymer chains of the crosslinked network around one another, progressively increasing writhe, tightening entanglements, and causing macroscopic contraction of the gel to ~70% of its original volume. Once the fuel supply is exhausted, contraction stops and the gel remains kinetically locked in a tensed, contracted state (no relaxation/re-expansion of the gel occurs over the course of several months). However, subsequent addition of the opposite enantiomeric fuelling system powers rotation of the motor-molecules of the contracted gel in the reverse direction, unwinding the entanglements and causing the gel to re-expand. Once the strands have unwound (and the gel has expanded back to close to its original volume), continued powered twisting of the strands in the new direction causes the gel to contract once again.

The catalysis-driven molecular rotary motor

The motor-molecule catalyses a carbodiimide-to-urea fuel-to-waste reaction,[7] transiently forming an anhydride in which the motor accesses a different set of conformational dynamics to those available in the diacid state. Use of a chiral carbodiimide and a chiral hydrolysis promoter introduces kinetic asymmetry in the chemomechanical cycle,[5,8] resulting in continuous directionally biased 360° rotation of the rotor about the stator.

The motor was incorporated into a polyethylene glycol gel by chemical crosslinking of the polymer chains at the motor nodes (Fig. 1a). A thin square of the gel (gel 1; ~10×10×1 mm) was treated with a solution of chiral hydrolysis promoter (S)-4 followed by chiral carbodiimide (S,S)-2. Contraction of the gel then occurred (Fig. 1b; Video 1), resulting in contraction of the gel to ~70% of its original size. Even after the gel stopped contracting, catalysis of carbodiimide hydration by the gel-embedded motors continued as long as unreacted fuel remained or if the fuel was replenished. Use of a fuelling system of the opposite chirality contracted the gel at the same rate by twisting the polymer strands in the opposite direction (Video 2). Treating the motor-incorporated gel with an achiral fuelling system (which cannot cause directionally biased motor rotation) did not lead to gel contraction, despite efficient catalysis of the fuel-to-waste reaction still occurring.

Fig 1: Contraction of a polymer gel with a covalently embedded chemically fuelled molecular rotary motor. a, Chemical structure of motor 1 and its conversion into a cross-linked gel (gel-1) with motor units at the reticulation nodes, through copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) with azide-terminated PEG chains. b, Treatment of gel-1 with chiral fuel (R,R)-2 and chiral hydrolysis promoter (R)-4 leads to clockwise rotation of the motor components through the motor’s catalysis of carbodiimide-to-urea hydration[6]. This winds the polymer chains around each other, increasing writhe and creating new physical entanglements, resulting in contraction of the gel. The (R,R)-2 and (R)-4 fuelling system causes biased clockwise rotation of the pyrrole rotor about the phenyl stator in gel-1, increasing writhe in a (+)-helical sense in the polymer strands.


Video 1: Contraction of gel through clockwise twisting of the polymer chains (producing (+)-writhe) with the (R,R)-2/(R)-4 fuelling system.


Video 2: Contraction of gel through counter-clockwise twisting of the polymer chains (producing (–)-writhe) with the (R,R)-2/(R)4 fuelling system.

The rheology of gel contraction (nanometre-scale structural effects)

The rheology of the motor-incorporated gel was compared before and after fuelling (Fig. 2). The storage (elastic) modulus (G′) of the gel was 4.7x higher in the contracted gel. The storage modulus is proportional to the number of crossings multiplied by the elastic energy per chain,[9] so the 4.7-fold increase in G′ indicates that the fuelled motor rotation produced a 4.7-fold increase in the number of twists in the polymer chains of the gel (i.e. each motor turns on average 4.7 times during the fuelling experiment).

Fig 2: Variation in G′ (storage modulus) and G′′ (loss modulus) before and after get contraction.

Atomic force microscopy (AFM) of gel contraction (micrometre-scale structural effects)

Effects caused by the twisting of the polymer strands in the fuelled gel were also evident at the microscopic scale (Fig. 3). Atomic force microscopy (AFM) images of the gel surface show changes in polymer chain conformation compared to the unfuelled gel, with the appearance of numerous kinks after contraction reflecting an increase in writhe (i.e., polymer chain twists). The reduction in surface homogeneity and the appearance of micrometre diameter pores in the gel after fuelling are a result of the winding of the polymer chains around each other generating large spaces empty of material in between denser, highly entangled, regions. Upon re-expansion of the gel (refuelling with an achiral fuelling system allows the high energy twists to untwist) the microscopic structure of the gel reverts to being similar to that of the unfuelled gel.

Fig 3: AFM comparison of gel before and after chemically fuelled contraction with a chiral fuel and subsequent re-expansion with an achiral fuel.

Tensile strength of gel contraction (macroscopic structural effects)

Tensile tests show that the Young modulus (E′) of the contracted gel (4.9 kPa) is higher than that of the unfuelled gel (2.1 kPa), consistent with the formation of new entanglements by fuelling (Fig. 4). The stress-at-break reaches ~2.5 kPa for ~110% of elongation for the unfuelled gel and for ~50% in the contracted form.

Fig 4: Variation in Young modulus (stress/strain, E′) before and after gel contraction.

Chemomechanics at the stall force

The point at which gel contraction stops in the chiral fuelling experiments, despite fuel remaining and catalysis continuing, corresponds to the stall force of the gel motors, a typical performance characteristic of motor proteins.[1] For the synthetic motor-molecules gel contraction stops when the unravelling force exerted by the twisted polymer strands and the osmotic pressure from gel contraction equal the directional bias for rotation of the motor-molecules under catalysis (i.e. the directional bias of the two Curtin-Hammett kinetic resolution steps in the catalytic cycle).

Powered re-expansion of the contracted gel


Video 3: Powered contraction of the gel with the (S,S)-2 and (S)-4 fuelling system, followed by powered re-expansion and subsequent re-contraction of the gel with the (R,R)-2 and (R)-4 fuelling system. Video credit: Dr. Anna Tanczos, SciComm Studios.

The ability to select the direction of rotation of the motors according to the handedness of the fuel allows the macroscopic gel contraction to be reversed by powered unwinding of the polymer chains (Fig. 5; Video 3). After contraction of the gel to ~70% of its original size by fuelling with (S,S)-2 and (S)-4 (anti-clockwise rotation that produces (−)-twists in the polymer strands. The waste and residual fuel and reagents were washed out of the contracted gel and the (−) writhe-contracted-gel was re-swollen in solvent and (R,R)-2 and (R)-4 added to power catalysis-driven rotation of the gel-embedded-motors in the opposite direction (i.e. clockwise). Under this fuelling regime, the (−)-writhe-contracted-gel first expanded over 5 h and then the gel begins to contract again, reaching a minimum volume of 62% after ~60 h of fuelling with (R,R)-2 and (R)-4. The powered re-expansion–re-contraction of the contracted gel was, again, accompanied by the closing and re-opening of micrometre-scale pores observable by AFM.

Fig 5: Chemically fuelled expansion–re-contraction of fuel-contracted gel. The gel is first fuelled with (S,S)-2/(S)-4 fuelling system (counter-clockwise motor rotation; blue data points in (c)), contracting the gel by twisting the polymer stands to produce (–)-writhe. The resulting waste and remaining fuel is then washed out of the contracted gel before it is refuelled with the (R,R)-2/(R)-4 fuelling system (clockwise motor rotation; red data points in (c)). This unwinds the (–)-twisted strands causing the gel to initially expand. However, once the stands are unwound further clockwise rotation by the motors continues to twist the strands in the new direction, generating (+)-writhe and causing the gel to contract once again.

Chemical effect of the elastic energy stored in the twisted chains of the contracted gel

Notably, the rate of re-expansion of the gel (Fig. 5c, red data points 0-5 h) is considerably faster than the rate of the subsequent (red data points 5-100 h) or original (blue data points) contraction. This is because the re-expansion is accelerated by the untwisting force exerted by the twisted strands improving the stereochemical bias of the chemically gated steps of the motor rotary catalysis. The release of elastic energy stored in the contracted gel to accelerate this process is a direct consequence of energy being transduced from the fuel-to-waste reaction by motor rotational catalysis during the first fuelled contraction

The results of this study are important and wide-ranging for several reasons:

(i) This is the first example of an artificial catalyst performing mechanical work (and generating force) through its catalysis of a chemical reaction—the same process that underpins the operation of motor proteins.

(ii) The simplicity of the synthetic molecule means that the chemomechanical mechanism of how energy is transduced by the catalyst to generate force and perform work is clear.

(iii) Because the directionally biased conformational changes in the catalysis mechanism occur between enantiomeric conformations, there is no power stroke in the mechanism. The experimental demonstration that a power stroke is unnecessary for mechanical force to be exerted by molecules through ground-state conformational dynamics has relevance for the dispute surrounding the mechanism of force generation by molecular motors.

The experimental demonstration of the transduction of chemical energy to perform work against a load through kinetic asymmetry provides a minimalist mechanistic illustration of how catalysis-driven molecular motors extract order from chaos.[2]

References

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2. Hoffmann, P. W. How molecular motors extract order from chaos (a key issues review). Rep. Prog. Phys. 79, 032601 (2016).

3. Amano, S., Borsley, S., Leigh, D. A. & Sun, Z. Chemical engines: driving systems away from equilibrium through catalyst reaction cycles. Nat. Nanotechnol. 16, 1057–1067 (2021).

4. Wang, P.-L., Borsley, S., Power, M. J., Cavasso, A., Giuseppone, N. & Leigh, D. A. Transducing chemical energy through catalysis by an artificial molecular motor. Nature 637, 594–600 (2025).

5. Borsley, S., Leigh, D. A. & Roberts, B. M. W. Molecular ratchets and kinetic asymmetry: Giving chemistry direction. Angew. Chem. Int. Ed. 63,e202400495 (2024).

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9. Colard-Itté, J.-R. et al. Mechanical behaviour of contractile gels based on light-driven molecular motors. Nanoscale 11, 5197–5202 (2019).