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Molecular machines Welcome to the machine Molecular machines have promised so much but are they more whimsical than technical? Philip Ball investigates

Hardly an issue of any major be confused with what really goes journal passes without In short on at the molecular scale. When reporting some new molecular  Molecular machines talk of making molecular ‘machine’ or ‘device’. They are tend to bear very little cars, elevators and trains they are often staggering in their ingenuity resemblance to the offering a convenient picture of and capabilities: they can crawl devices that they are what they have devised; it doesn’t over surfaces, flex like muscles, named after mean that they have exact, miniature even perform arithmetic and  After two decades analogues of these macroscale computation. They seem to tell of research, molecular devices. us that chemistry has become a machines are still of Take the molecular elevator kind of scaled-down mechanical limited use, but the field devised by , now engineering. is moving on rapidly at Northwestern University in But how far does that analogy  Nature is providing Evanston, US, in collaboration with really apply? And are these inspiration for many of Vincenzo Balzani, Alberto Credi molecular machines anything more today’s researchers and colleagues at the University than just whimsical demonstrations  Large assemblies of of Bologna in Italy. In this device, of technical prowess? Indeed, are machines could be the three hoops on the elevator stage they truly machines at all? In a field way forward are threaded by the tripod legs of the that is arguably now at least two frame. Each hoop may be switched decades old, it may be time to take between two docking stages by stock of what has been achieved, protonation: by adding acid. It’s what the limitations are, and where tempting to think that this means the the work is headed. elevator can be sent from one ‘floor’ to another on command. That’s Moving parts kind of true, but it is really only When surveying modern research an equilibrium ruffled by thermal on so-called molecular machines, fluctuations. At any moment, most the machine metaphor should not of the elevators are at the bottom

56 | | January 2010 www.chemistryworld.org ‘Molecular floor in acid and the top in basic by interdigitation of protein strands conditions. But any specific elevator in the presence of calcium . machines is liable to switch at any moment. Robert Grubbs and coworkers at the must work in a Imagine that on the 33rd floor of the California Institute of Technology, Hilton. US, have recently made ‘daisy-chain’ maelstrom’ This points to the key distinction in which a whole series between molecular and macroscopic of these units is linked together. machines. Without fuel or power, In theory, Grubbs and colleagues the latter lie inert. But molecules estimate that a perfectly linear are never still: under the influence of this sort should be 58 per of thermal noise and molecular cent longer in the extended state collisions, they are constantly in than when contracted. Over many motion, always changing shape. So monomer units, that difference will molecular machines must, in effect, add up to an appreciable absolute work in a maelstrom. displacement of the ends. Clearly, this needn’t prevent things from getting done. In the Open on command cell, motor-borne cargo reaches its Switchable molecular mechanics destination, valves and gates succeed is itself old hat: heat and light, for in regulating trans-membrane example, have long been used to traffic, life goes on. But it does so in induce transitions between isomeric a noisy manner. So what, then, can forms of a molecule that involve we expect of molecular machines, changes of shape. For example, and what can we realistically do with a carbon–carbon or nitrogen– them? And how can we design them nitrogen double bond can be rotated to be reliable in the buzzing world of 180° by ultraviolet (UV) light or heat, the molecule? to give cis or trans isomers. In this way, the two groups are brought Shuttle service closer together or further apart. The molecular elevator stems Jeffrey Brinker and coworkers at from one of the first molecular Sandia National Laboratories in constructions to be presented as a Albuquerque, US, have used this mechanical device: the molecular principle to make light-switchable shuttle, which Stoddart and his valves for opening and closing the coworkers made in 1991 while he channels of a porous form of silica. was at the University of Sheffield, They coated the pore walls with UK. This was a rotaxane – a threaded azobenzene molecules, which hoop-and-axle molecule – with two have photoisomerisable nitrogen– potential docking ‘stations’ on the nitrogen double bonds. In the cis axle where the hoop could reside. form, produced by UV radiation, the To turn molecular into large-scale pendant molecules are shorter and motion, Stoddart and colleagues leave an open channel in the centre have coupled bistable rotaxanes to of the pores, whereas restoring the microscopic silicon cantilevers so trans form using heat or green light that the switching makes the levers switches the molecules back to a bend: a sort of molecular muscle. pore-blocking state. They strung two hoops on an axle While at the University of with four stations, and chemical California, Los Angeles, US, Stoddart oxidation promoted movement of teamed up with Jeffrey Zink to the hoops from the two end stations devise similar switchable molecular to the two in the middle. Because valves based on pseudorotaxanes, in the hoops were covalently tethered which the hoop can spontaneously to the cantilever surfaces, bringing unthread. They found that nanoscale them closer together tugged on pores could be blocked by a the cantilevers, making them bend pseudorotaxane at the pore mouth, upwards by about 35nm – a much and opened by triggering release of larger displacement than that of the the hoop. Stoddart and Zink recently hoops. made a more biocompatible version: Jean-Pierre Sauvage at the hollow silica nanocapsules with University of Strasbourg in France porous walls through which the has explored a related ‘molecular release of encapsulated molecules muscle’ concept in which two can be triggered by pH-dependent hoops are mutually threaded onto formation of threaded molecular shafts attached to the hoop of the complexes with hoops of sugar other molecule. The two hoops are molecules called α-cyclodextrin Molecular elevators pulled towards one another when (α-CD). These sit on short stalks can’t really move reliably the device is supplied with metal topped with aniline groups, attached between ‘floors’. They ions. This metal-triggered sliding at the pore mouths. When the can switch at any time mimics the way muscles contract α-CDs are threaded, the pores are www.chemistryworld.org Chemistry World | January 2010 | 57 Molecular machines

blocked, preventing dye molecules top of the film, would ‘surf’ these inside from escaping. Adding acid undulations and rotate with them. protonates the aniline groups, Feringa’s motors exemplify which kicks off the α-CD the principles for achieving caps, opens the pores, unidirectional behaviour at the and releases the dye. molecular scale: an energy This sort of controlled source provides the impetus, release might be used and geometric asymmetry to deliver drugs to defines the direction. specific targets in the The classic example JOURNAL OF THE AMERICAN CHEMICAL SOCIETY CHEMICAL AMERICAN THE OF JOURNAL body, such as cancer of this kind of process cells. invokes a particle diffusing by random Molecular ratchets Brownian motion One thing that over parallel ridges. distinguishes these If the ridge profiles gates and valves have an asymmetric, from real machines sawtooth form, then is that they don’t it is easier for the get anywhere: the particle to move down moving parts simply the shallower slope than flip back and forth. In to surmount the steep one, everyday engineering, we and so there is net motion in can turn that sort of repetitive one direction. This is called a movement into unidirectional Brownian ratchet. motion: it’s what happens in a The directional motion can’t be pendulum clock. The key there is driven by thermal or Brownian the rack-and-pinion mechanism, fluctuations alone. Brownian which is a kind of ratchet in which ratchets need some external energy asymmetric, sawtooth-shaped teeth source such as a thermal gradient only allow rotation in one direction. or a fluctuating fluid flow to drive In other words, symmetric motion is rotors in which the two blades Controlled release the system away from equilibrium. made directional by an asymmetric had different structures, allowing of drugs from hollow At the molecular scale, chemical geometry. them to be targeted independently. nanoparticles triggered reactions can supply the necessary Ten years ago, Ben Feringa They could fix one blade to a gold by molecular valves could energy input, and this is how at University in the surface while the other blade was be the key to smart drug molecular motors and propulsion Netherlands realised that the left to rotate freely. Fine-tuning this delivery devices typically take advantage of rotation of molecular groups design has led to molecular rotors the ratchet principle. entailed by cis–trans isomerisation that will spin at nearly 10 million Brownian molecular ratchets are could be made directional by revolutions per second at room found in nature. The movement of attaching an asymmetric structure. temperature. RNA polymerase on DNA during This enabled him to make the first Feringa and colleagues have used replication seems to work this way, unidirectional artificial molecular these motors to rotate much larger progressing steadily in the same rotor from a molecule containing objects. They found that the light- direction. two identical propeller-like triggered rotation could influence Haiping Fang and colleagues at blades linked by a carbon–carbon the molecular organisation of a the Institute of Applied double bond. The key was that film when the motors This light-driven Physics in used Brownian the blades had to twist slightly to were added as a dilute dopant. will ratcheting to propose a kind of avoid bumping into each other at This allowed them to rotate the rotate the texture of molecular pump made from a their ends, and this gave the whole fingerprint-like furrows that appear a liquid crystal film, carbon nanotube. They considered a molecule a twist: it was chiral. This on the surface of the film. And a causing a 28µm floating nanotube embedded in a membrane biased the isomerisation process, microscopic glass rod, 5mm across glass rod to rotate with it matrix, through which water so that continual irradiation with and 28mm long, floating on the molecules can pass in a hydrogen UV light could, if accompanied bonded chain. Because water is by enough heat, allow the polarised, three positive charges molecule to rotate continuously placed asymmetrically outside a in one direction. Feringa and his carbon nanotube can pump water colleagues subsequently made through the tube in one direction. These charges might be provided by chemical groups attached to the nanotube, or by tiny electrodes in NATURE the membrane matrix. Because the nanotube is so narrow, salt ions can’t pass through without losing their hydration shell. This costs too much energy, so salt is essentially excluded from the flow, making the construct (still hypothetical) a potential nanoscale desalinator. 58 | Chemistry World | January 2010 www.chemistryworld.org and living organism,’ says Feringa, for example in cell division, motion, signal transduction and mass transport. And they are efficient devices. ‘I can do things with kinesin motors which are orders of magnitude faster, more specific and more powerful than what one

JOVICA BADJIC AND FRASER STODDART FRASER AND BADJIC JOVICA can do with rotaxanes,’ says Hess. However, he admits that ‘my hybrid solutions are still far away from application-ready, due to their limited stability’. DNA offers perhaps the best of both worlds. It can be assembled, manipulated and even replicated with existing biological components. And it can be twisted and bent and looped into all manner of shapes. It has already been used to make a wide variety of molecular machines. For example, Bernard Yurke of Bell Laboratories in Murray Hill, New Jersey, US, Andrew Turberfield of the University of Oxford, UK, and their coworkers, made a DNA machine shaped like a pair of tweezers that could be switched between a compact and open form by adding two single DNA strands in succession. A ‘fuel’ strand binds to part of the machine to which its sequence is complementary, It’s likely that motor proteins climb up sharp inclines, embossed Fraser Stoddart (right) producing a shape change. It is harness Brownian ratcheting to patterns on the surface stay dark examining his molecular then peeled off to restore the initial achieve directional motion. For in time-averaged images. Hess and elevator conformation by the second strand, example, the protein kinesin, which Vogel have grown microtubules a kind of ‘anti-fuel’. The fuel strand tows organelles as it ‘walks’ along from the component tubulin has a few bases left dangling on microtubules, uses the binding of proteins within microfabricated which the anti-fuel strand can get a one of its two ‘legs’ to the track to polymer channels on glass, thereby foothold to start stripping it away. bias the diffusional search of the creating patterned tracks on which The researchers subsequently other leg for a binding site in the they use kinesin to transport figured out how to make DNA forward direction. fluorescent nanoparticles in a machines that switched their Viola Vogel, now at ETH in directional manner. In this way they conformation repeatedly in Zurich, Switzerland, Henry Hess made molecular roundabouts which a free-running manner when at the University of Washington in look like highway roundabouts seen provided with the fuel and anti- Seattle, US, and their coworkers, from above at night. fuel strands, without the need for have shown that kinesin molecules And last year Hess and his the experimenter to intervene anchored on a solid surface can coworkers described a ‘smart dust’ constantly to complete the cycle. pass microtubules around. They device in which microtubules Nadrian Seeman at New York bound the kinesin to films of would capture an analyte in one University, US, and his colleague polytetrafluoroethylene containing region and carry it over a kinesin- William Sherman have used the striated grooves and ridges on which coated surface to another region same principles to make a DNA the proteins bind preferentially for fluorescent labelling, and then biped – two double helical legs at low concentrations. This sets to another for detection with light. connected by flexible linkers and up linear tracks of motors for This removes the need for separate ending in single-stranded feet – that propelling adsorbed microtubules. washing, tagging and detection ‘walks’ along another DNA strand. The researchers later transported steps in conventional assays: the The footpath contains a series ‘cargo’ (nanoparticles) attached to molecular machinery does it all. of toeholds with dangling single microtubules. strands, to which one of the biped’s The team has been putting its DNA on the move ‘Molecular feet can be bound by adding a set molecular transport system to So if we are interested in getting the machines strand on which half the sequence ingenious uses. It exploited the job done rather than in exploring is complementary to the free strand random motions of fluorescently and extending the limits of synthetic will have to on a particular toehold and the labelled microtubules to generate chemistry, it might make a lot of be organised other half is complementary to the images of surface topography with sense to use nature’s molecular dangling foot sequence. The foot is a resolution of less than 50nm: machines. ‘Motors are involved in into large released by adding an unset strand because the microtubules can’t nearly every key process in the cell assemblies’ that peels off the set strand, starting www.chemistryworld.org Chemistry World | January 2010 | 59 Molecular machines

from a region left unpaired at the how much force can they produce, end of the foot. and how quickly, and at what energy If, however, the toeholds of cost? Initial rough estimates don’t the path are all equivalent, then bode well. For example, a polymer a walker of this sort will simply molecule containing 20 light- move at random along it. And if switchable azobenzene pivots can the detachment of one leg is not perform only about 4.5 × 10–20J coordinated with the attachment of of work per azobenzene, which the other, there’s no guarantee that is scarcely more than the thermal the walker will remain fixed to the noise. However, other devices path at all. These limitations have pack more of a punch: a switchable recently been overcome by Seeman rotaxane might produce a factor of and colleagues, who designed a several tens of the thermal energy walker in which the motion of the per molecule. And if large arrays of legs is coordinated: the leading leg molecules can be organised so that catalyses the release of the trailing they all act in concert, as they do in leg. This stepping cycle is triggered muscle, then the collective force can by fuel strands, and it relies on the Ben Feringa used be substantial. track itself being asymmetric, with cis–trans isomerisation Considerations like this lead non-equivalent toeholds. In this to make artificial rotors Stoddart to think that molecular way the DNA walker becomes a machines whose purpose is to Brownian ratchet. It’s an ‘expensive’ advantages. ‘All living organisms induce motion at scales much larger stroll, however, because each rely on sunlight as the primary than themselves will have to be toehold is in effect destroyed when energy source,’ he points out. Light organised into large assemblies. stepped on: the walker burns is clean and abundant. In contrast, ‘a ‘Single artificial motors swimming its bridges. So we have a way to device that utilises chemical energy around aimlessly in solution are go yet before we can mimic the will need addition of fresh reactants going nowhere fast,’ he says. ‘We coordinated motion exhibited by at any step of its working cycle, with have really got to move on into new kinesin on conserved microtubule the concomitant formation of waste arenas, into extended structures, tracks. products.’ What’s more, he says, into one- and multi-dimensional the energy input can be carefully polymers, onto surfaces, into Working together controlled by the wavelength and interfaces, and so on. Intuitively, Feringa foresees a shift in chemistry intensity of the exciting photons. one feels as the cooperative and microphysics, away from static, And this energy ‘can be transmitted systems grow in size, the thermal equilibrium systems and towards to molecules without physically fluctuations that undoubtedly dynamic ones. ‘Out-of-equilibrium, connecting them to the source – no dominate the small molecular kinetically driven, dynamic systems ‘‘wiring’’ is necessary’. world will surely start to become governed by switches, triggers, Stoddart thinks that the most less important, and ultimately will response elements and motors will useful machines may be ones that, more or less peter out.’ Then we’ll change drastically our approach while perhaps inspired by nature, be getting somewhere. to smart, responsive and adaptive do not follow their design too materials, devices and , slavishly. ‘My ’s view is that Further reading computation, and so on.’ we need to go down a road involving J D Badjic et al, Science, 2004, 303, 1845 Now that molecular engineers are construction that is much more S Silvi, M Venturi and A Credi, J. Mater. Chem., almost spoilt for choice, they need robust in a skeletal sense than we 2009, 19, 2279 P G Clark, M W Day and R H Grubbs, J. Am. to consider their options carefully. see in nature,’ he says. Chem. Soc., 2009, DOI: 10.1021/ja905924u What are the most robust and And how might we want to use R Hernandez et al, J. Am. Chem. Soc., 2004, reliable fabrics for making these such machines? In biology, they may 126, 3370 devices, and how might they best power macroscopic devices, such as The DNA biped in action, M Klok et al, J. Am. Chem. Soc., 2008, 130, 10484 be powered? Balzani thinks that an arm or leg. But for applications walking along a track of H Hess et al, Nano Lett., 2002, 2, 113 light-driven systems have several like that, three key questions arise: three footholds V Balzani, Chem. Soc. Rev., 2009, 38, 1542 NANO LETTERS NANO

60 | Chemistry World | January 2010 www.chemistryworld.org