A few weeks ago we noted the publication of a tutorial review that asks whether artificial molecular machines can deliver the performance that visionaries expect. Upon learning that the full text is available after a free registration, I downloaded the review to learn what the authors think about the prospects of eventually doing atomically precise manufacturing with artificial molecular machine systems.

The authors begin with the observation that, despite “remarkable progress” in synthesizing molecular switches, there have been only few and very rudimentary examples of harvesting useful work from such molecular switches. They then ask whether only incremental progress will be necessary for artificial molecular machines to achieve the levels of function so elegantly achieved by biological molecular machines, or whether some paradigm shift in thinking will be necessary (they believe the latter).

The fundamental theory of molecular machines is applied to two questions. (1) Can artificial molecular machines be developed to manipulate or chemically transform other molecular or nanoscale structures? (2) Can artificial molecular machines be assembled into integrated systems that work together to manipulate or fabricate structures at the meso- and macroscopic levels? The overall conclusion of these authors with respect to these two questions is optimistic:

Indeed, nanoscale-based machinery has been envisaged ever since the days of Feynman and today the Feynman’s Grand Prize offers a $250,000 reward to the first persons to create a nanoscale robotic arm, capable of precise positional control. While, in pursuit of this goal, the “top-down” fabrication strategies have so far failed rather dismally, we are convinced that a “bottom-up” approach, utilizing AMMs [artificial molecular machines], can deliver. Engineering a macromolecular architecture capable of robotic function will no doubt be a considerable synthetic challenge. We feel, however, that the time is ripe for such an undertaking—for instance, by combining AMMs with the DNA-origami materials, such that the former would provide the actuation within precisely folded DNA nanoscaffolds of the latter.

A major focus of this tutorial review is to describe the recently developed theoretical concepts “that distinguish simple molecular switches from fully fledged molecular machines.” Simple molecular switches differ from familiar macroscopic switches in that the switching between the states of the switch is driven by thermal noise. To advance from simple molecular switches to molecular machines, it must be possible to drive chemical reactions uphill, away from equilibrium, as do biological motor molecules. This can be accomplished by using molecular switches to alter the energy profile of the reaction by first lowering the energy of the intermediate to be less than the energy of the starting material, and then switching again to raise the energy of the intermediate above that of the product, and finally switching again to reset the system to the original energy profile. Switching makes each molecular transformation along the way spontaneous, but the end result is shifted way from the equilibrium without switching.

The authors give the example of doubly stable bistable rotaxanes—dumbbell-shaped molecules in which an electrochemical input can move reactants to different positions along the central part of the dumbbell to alter an energy profile and drive a reaction uphill. An example is given of a molecule that can be switched by an oxidation-reduction event between contracted and extended states. If such a molecule is attached to a molecular spring, then the extended form of the molecule could store energy in the spring molecule. If the architecture of the device as a whole allows the spring to be detached from the oxidation-reduction switch, then the energy stored in the spring can be harvested to do external work. Thus an oxidation-reduction switch becomes part of a simple molecular motor.

Having considered how to extract external work from externally switchable molecules, the authors consider how sufficient energy to perform macroscopic work could be harvested from mesoscopic arrays of AMMs. They note that in biological systems molecular motors are organized spatially and synchronized to act together, and consider approaches to fabricate such arrays through self-assembly. They cite metal oxide frameworks as one potentially promising type of scaffolding that might be used to array AMMs.

The brief roadmap presented in this tutorial review outlines the challenges and opportunities involved in transforming simple molecular switches into AMMs. The authors are optimistic:

On the horizon lie new types of “mechanized” enzyme-like mimicks, addressable nanomaterials, nanorobots, and possibly more into the bargain.