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Rethinking Molecular Machines

Makers of artificial molecular-scale devices grapple with how to make the field achieve its promise

by Bethany Halford
April 2, 2012 | A version of this story appeared in Volume 90, Issue 14

Structure of a hypothetical molecular machine that would perform a reverse Diels-Alder reaction.
This hypothetical molecular machine performs a reverse Diels-Alder reaction.

One of the great joys of being a chemist is making stuff. Like architects working on the smallest of scales, chemists can create the most ingenious molecules, limited by only their imaginations and the rules of chemical bonding. Perhaps nowhere is this creativity of synthetic chemistry more evident than in the field of artificial molecular devices—where single-molecule ratchets spin, motors whir, and machines maneuver all by virtue of chemical reactions and interactions.

But after two decades of molecular whirligigs and doodads, Northwestern University’s J. Fraser Stoddart, one of the field’s leading researchers, and his Northwestern colleague, Bartosz A. Grzybowski, an expert in nonequilibrium chemical systems, are taking a hard look and asking, “Can artificial molecular machines deliver on their promise?”

That provocative question is the subtitle of an article the two published, along with Ali Coskun of the Korea Advanced Institute of Science & Technology; R. Dean Astumian of the University of Maine, Orono; and Michal Banaszak of Poland’s Adam Mickiewicz University, late last year in Chemical Society Reviews (DOI: 10.1039/C1CS15262A). The chemists who construct these molecules hope the compounds one day will be able to do useful work beyond the molecular scale. They point to kinesin, the motor protein that transports cargo in cells by “walking” along microtubules, as a prime example of what a molecular machine can do. Ideally, these chemists would like to make molecules that can accomplish similar tasks, such as transporting molecular cargo or powering movement in artificial muscles.

But artificial molecular machines cannot yet do any of these things.

One of the chief problems, argue the review’s authors, is that chemists haven’t actually made very many molecular machines. “In the early days everybody in the field, if they had something that moved, they would call it a machine,” Stoddart says. But machines, he says, have to do work on their environment, and most of the so-called machines that chemists have invented are, in fact, just switches that move from one state to another and back again without having a net effect on their surroundings.

“How can you possibly get any useful work, any net displacement, anything that is really machinelike if you’re based on fully reversible motion?” Grzybowski asks. “That’s the major problem of this entire field.” As beautiful as these systems are, he says, “by themselves these things are totally useless. They will never be machines.”

“Switches are a dime a dozen,” Stoddart adds. There are some rudimentary examples of actual molecular machines that move objects on the macroscopic scale, he says. His group made a molecule that bends a microcantilever. Others, such as Ben Feringa’s group at the University of Gro­ningen, in the Netherlands, have made unidirectional molecular rotary motors that spin macroscopic objects and propel nanoparticles in solution. But these examples, Stoddart says, are few and far between.

If artificial molecular machines are ever going to be as useful as their biological counterparts, the people that create them need to change their way of thinking, argue Stoddart, Grzybowski, and their coauthors. Otherwise these chemists may be left making cleverly conceived molecules with no further purpose than to look good. And interest in the field may simply fizzle out.

For molecular machines to actually accomplish work, Grzybowski says, they need to interface with their environment—attach and detach so that they do work on their surroundings, as opposed to simply moving back and forth. And in order to design machines that do work on their environment, chemists who make molecular machines must understand the underlying physics of the molecular world.

“If you look in the literature, you will see that molecular machines are often described, more or less, as shrunk-down versions of macroscopic machines,” says Astumian. “The physics is all wrong.” For example, he says he came across a paper in which one particular movement of kinesin’s motion along a microtubule track is described as a judo throw. This makes no sense, Astumian says, because the viscosity that kinesin experiences from its surrounding solvent is so great there is effectively no inertia. In the molecular world, he says, objects in motion tend to stop instantly because of viscosity. Movement for a molecule in solution, he says, is like swimming in molasses.

“There’s a kind of misunderstanding in the literature that if we design molecules that are stiff and operate as springs that we’ll be able to design more efficient machines. That’s just not true,” Astumian continues. “We don’t need levers, cogs, and all of these little devices from the macroscopic world shrunk down. What we need is the ability to control the lability of molecules—how fast they react back and forth—and the stability of molecules, which ones are more or less favored in equilibrium.”

The opinions of the review’s authors diverge when it comes to answering their own titular question. Astumian’s answer is yes, but only if scientists begin to challenge such machines with appropriate single-molecule tasks. “I think that molecular machines have a huge potential to revolutionize the way that we make novel chemical products,” he says. For example, he explains, we need devices that are able to make Diels-Alder reactions go backward or devices that can place atoms in proximity so that they react.

Stoddart also answers the question in the affirmative, but he has bigger plans. He envisions creating arrays of millions of machines and interfacing them with polymers so that the machines move simultaneously to do work on a macroscopic scale.

Grzybowski is more circumspect in his response. “For the development of chemistry, for the development of self-assembly, for the development of nonequilibrium thermodynamics applied to molecules, I think that making molecular machines is still a very good challenge,” he says.

But as far as making something as advanced as kinesin, he’s doubtful. “What I don’t like about most of these little machines is that they work in certain environments, such as acetonitrile.” If they are ever going to make an impact, he says, these machines have to be water-based so they are biocompatible, they have to work at room temperature, and chemists have to figure out a way to orient 1020 of them on a surface and get them all to move synchronously.

Other molecular machine makers are calling the review a welcome call to assess the state of the field. “I think it’s very timely that we ask ourselves the questions, ‘What are the key problems to address in the next years?’ and ‘Can we get something useful out of this?’ ” Feringa says. “We have to work extremely hard to get all the parameters right—the collective behavior, the integration with surfaces, interfacing with the macroscopic world, the durability, and integrating of different functions.”

“I sincerely believe that synthetic molecular machines are going to revolutionize everything,” adds David A. Leigh, a molecular machine maker at the University of Edinburgh, in Scotland. “I think that when chemists learn to control molecular motion in the same sort of way that biology does, then I have absolutely no doubt that it will change our whole approach to functional molecule design, whether it’s in pharmaceuticals, catalysts, or materials.”

But he agrees that the field has a long way to go. Asking how chemists will realize the dream of making systems as sophisticated as those in biology, Leigh says, “is a little bit like asking a Stone Age man who has come up with the wheel and the axle how he’s going to build a motorcar. We’re at the stage where people have made wheels, switches, and rotary motors. The next stage is to learn how to put those things together in a way that can produce a useful function.”


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