Catalysis of this reaction proceeds through a four-step cycle consisting of two chemical transformations (ester formation and ester hydrolysis) that occur at different rates depending on the two conformational states of the ratchet. The stochastic exchange between these conformations during the cycle happens at a twofold higher rate than the chemical steps, which become the rate determining steps. After performing a series of control experiments, the researchers found that the designed organocatalyst accelerates the reactions via stochastic exchange, with higher rate accelerations compared to static and single-conformer controls. Further, the reaction does not require external energy input, as in the case of many heterogenous catalytic processes. Finally, since the ratchet performs one net directional rotation every six catalyst turnovers, this cycle can be seen as a chemomechanical one, which the team liken to that of a small motor fuelled by carbodiimide hydration.
Conformational selection is an untapped design feature that can be used to improve reactions thanks to faster reaction catalysis. At the same time, the directional bias resulting from the fastest route to sample the catalyst’s active conformations establishes a link between dynamic catalysis and directional motion. This could have implications for the origin of self-replicating systems such as primordial forms of molecular motors, since faster catalytic systems may have become more abundant in the primordial soup and therefore provided evolutionary advantages.
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