Chemically Propelled Molecules and Machines - Journal of the

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Chemically Propelled Molecules and Machines Krishna Kanti Dey*,† and Ayusman Sen*,‡ †

Department of Physics, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar 382355, Gujarat, India Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States

‡

responding to their environment (sensor applications) without being tethered to a single power source or location. In this perspective, we focus on chemically powered motors and pumps at submicroscopic length scales. Motors are objects that can transduce chemical energy into mechanical motion through a variety of propulsion mechanisms. When these motors are anchored onto a surface, their mechanical energy is transferred to the surrounding fluid, making them function as miniaturized fluid pumps.

ABSTRACT: Self-propelled, synthetic active matters that transduce chemical energy into mechanical motion are examples of biomimetic nonequilibrium systems. They are of great current interest, with potential applications in nanomachinery, nanoscale assembly, fluidics, and chemical/biochemical sensing. Many of the physical challenges associated with generating motility on the micro- and nanoscale have recently been overcome, leading to the first generation of autonomous motors and pumps on scales ranging from microns to nanometers. This perspective focuses on catalytically powered motile systems, outlining major advances to date in motor/pump design, propulsion mechanisms and directional control, and intermotor communications leading to collective behavior. We conclude by discussing the possible future directions, from the fundamental questions that remain to be addressed to the design principles required for useful applications.

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NANOMOTOR DESIGNS: CHALLENGES AT LOW REYNOLDS NUMBER In the natural world, controlled motion at the nano and micron scale is ubiquitous. Motor proteins power the motion of bacterial flagella and cilia, facilitating the movement of these tiny organisms through solutions.9 Some bacteria use short, hair-like appendages known as pili for movement, that binds to the host surface receptors and when retracted, pull the bacteria along the surface.10 Active ion pumps inside the cellular interior constantly transcribe chemical information by transporting various ions against chemical potential gradients; maintaining proper balance in intracellular osmolyte concentrations.11 Evolutions, however, had millions of years in optimizing the extraordinary range of biological innovations and tools. Lacking the luxury of time, we must take advantage of our ability to intelligently design potential motors. In such a task, we must consider the nature of physical laws operative at low Reynolds number regimes and their consequences on fluid motion and particle dynamics. Physics at submicroscopic length scales is usually dominated by shear forces parallel to particles’ surface rather than by inertial forces which scale with particles’ volume and which dictate their dynamics at the macroscale.12 Propulsion at micro- and nanometer length scales can therefore be achieved effectively by generating various shear force gradients across the particle surface. Additionally motions of tiny particles in fluids are influenced by Brownian forces, which results in erratic random walk like trajectories at longer time scales.13 The biological world is dominated by random thermal fluctuations but nature has developed machines that can rectify the fluctuations to do useful work (e.g., Brownian ratchets such as F0 motor in ATP synthase or actin).14 Molecules of kinesins and dyneins move along microtubules, and certain myosins are designed to move along actin filaments by overcoming the strong Brownian fluctuations, driving the intracellular traffic of vesicles and organelles with remarkable efficiency.15 Finally, several physical forces, which are negligible across long distances, begin to dominate on the nanoscale. Electrostatic forces

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INTRODUCTION We live in the information age, driven by the ability to communicate and integrate ideas. However, this is also the age of miniaturization, with the ability to fabricate, manipulate, and assimilate matter on the nanoscale facilitating the information exchange.1−3 While we have become quite adept at fabricating materials on the small scale and manipulating the flow of energy through them, the ability to precisely control the motion of the materials themselves is still in its infancy. Until recently, the work in this area has mostly focused on coaxing micro- and nanostructures to deform, rotate, and move repeatedly over well-defined molecular-scale distances.4−7The pioneering work in this area has led to the award of the 2016 Nobel Prize in Chemistry to Savage, Stoddart, and Feringa.8 This perspective focuses on a complementary, and arguably more challenging, avenue of research: How can we design populations of artificial micro- and nanostructures that can move autonomously over long distances, while at the same time have the ability to organize themselves on command to perform complex tasks. The potential applications of such synthetic interacting nano and micromachines would be almost limitless. Access to rationally designed dynamic materials that are capable of remodeling themselves and transforming their environment will (i) minimize waste (they will change their function and purpose rather than being of single-use), (ii) improve performance (they will continuously evolve their structures to optimize performance), and (iii) accomplish tasks collectively and emergently (like a colony of ants) that a single constituent element (like a single ant) cannot perform. By making these dynamic materials self-powered, they can be made capable of exploring and © 2017 American Chemical Society

Received: March 8, 2017 Published: May 11, 2017 7666

DOI: 10.1021/jacs.7b02347 J. Am. Chem. Soc. 2017, 139, 7666−7676

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Journal of the American Chemical Society

metric force fields of some nature around each particles in an assembly. In the presence of local force fields, the mobile ions within the interfacial layer of each particle move and cause liquid flow, making the particle drift in the opposite direction. Motions of this kind which arises due to forces operating within the interfacial layer of the particles, rather than on the bulk are called phoresis. Molecules and microparticles, capable of chemically interacting with their surroundings have recently been shown to self-propel using different phoretic mechanisms.25−27 As described below, this offers a range of possibilities to maneuver micro- and nanoscale particles in liquid independently, while simultaneously endowing them with specific functionalities in an assembly.

between charged objects, for instance, grow proportional to ΔR2 as the distance between objects is decreased. The (usually attractive) van der Waals interactions between an object and its neighbors, on the other hand, grow by ΔR6.16 This is the basis for the “sticky fingers” argument as to why it is physically impossible to build nano robots that reproduce themselves through atom by atom assembly.17 Nature of fluids at smaller length scales offers additional challenges in designing propulsion strategies for nanomotors. The systems are characterized by very low Reynolds numbers, and to achieve propulsion, it requires swimmers to deform in a way that is not invariant under time reversal. The Reynolds number (Re) of the particle, which is usually measured as the ratio of inertial to the viscous force, can be expressed as18

Re =

ρVL μ

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ELECTROPHORESIS Electrophoresis results when motion is induced in colloidal particles using electric fields. Dynamics of freely diffusing ions can also be influenced by external electric fields. For larger colloids, however, the mobile ions within the interfacial layer of a particle interact with the electric field, resulting in fluid flow around the particle surface. The fluid flow together with particle’s own electrostatic interaction with the field causes a steady drift of the particle with respect to the fluid layer. The electrophoretic speed of the particle can be calculated from the magnitude of the electro-osmotic flow around it, using the famous Smoluchowski equation:16

(1)

Here, ρ is the density of the fluid, V is the velocity of the particle relative to the fluid, L is the characteristic length scaleusually considered to be the dimension of the particle, and μ is the viscosity of the fluid. One far reaching consequence of low Re limit is kinematic reversibility, which facilitates laminar flow of liquids within narrow confinementsa property that has been extensively exploited in microfluidic devices.19,20 This has further been demonstrated by the famous Couette cell demonstration,21 where a drop of dye suspended in a high viscosity liquid is sheared between two concentric cylinders and stretched to wrap around the inner cylinder several times. The motion is then reversed which brings back the drop of dye to its original shape. This is famous Scallop theorem of Purcell22 and microscopic swimmers overcome this hurdle by many fascinating swimming strategies that break the time reversal symmetry at low Reynolds number. This is very different from the macroscopic world where owing to the dominance of inertial motion, reciprocal swimming strategies can lead to effective propulsion of objects in fluids.

U=

MECHANISMS OF MOTILITY AT MICRO- AND NANOMETER LENGTH SCALES Micro and nanoscale colloidal particles often have a few molecular layers of fluid pinned over their surfaces by strong van der Waal’s forces, resulting in what is known as the no-slip condition.23 Beyond this pinned layer, charged colloids are usually surrounded by a cloud of counterions forming what is known as the interfacial or double layer. The thickness of interfacial layer is decided by the particle surface charge and the local ionic strength of the medium, and is normally measured in terms of the Debye length (κ−1 by convention) of the particle, which in most systems lies within 1−100 nm.24 The Debye length can be calculated from eq 2,13

Figure 1. Schematic of Pt/Au bimetallic nanomotor fabricated by Paxton et al.28,30 The rods self-electrophoretically move in hydrogen peroxide solution by redox reactions occurring at their ends. Figure adapted from ref 30 with permission from the American Chemical Society.

catalytic decomposition of hydrogen peroxide results in the generation of an electric field, powering the nanorods.28,30 Mano et al. fabricated a bioelectrochemical motor by attaching two electrochemically coupled enzymes to the opposite ends of a carbon fiber.35 Several factors influence self-electrophoretic motility of particles including the fluid medium, solution viscosity and ionic strength.36

ε0εrkBT 2NAe 2I

(3)

Here ε is the permittivity of the solution, ζ is the zeta potential of the particle, η is the viscosity of the solution and E∞ is the electric field. The electric field can be external or generated in situ through redox chemical reactions. Self-electrophoresis has been demonstrated by several groups working on motors of different compositions and geometry.28−35 The initial Pt/Au nanorod motor discovered by Paxton et al. functions based on self-electrophoresis (Figure 1), where

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κ −1 =

εζ E∞ η

(2)

where ε0 is the permittivity of free space, εr is the dielectric constant of the electrolyte, kB is the Boltzmann constant, NA is Avogadro’s number, e is the charge of an electron, and I is the solution ionic strength. Each particle together with its interfacial layer is electrically neutral and, without any external field, is in equilibrium. However, they can be set into motion by a variety of external fields and most motility mechanisms involves generation of asym-

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DIFFUSIOPHORESIS The generation of ionic products by catalytic particles in a liquid has additional effects on the particle double layer. First, spontaneous electric field generated within the liquid by the diffusing ions can result in electrophoresis of the particles. Moreover, as mentioned earlier, the thickness of double layer 7667


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The parameter K is known as adsorption length, which physically signifies the strength of particle-solute interaction. Nonionic diffusiophoresis can also propel particles that generate local solute gradients via chemical reactions. Possible nonionic self-diffusiophoretic motion was demonstrated by Pavlick et al., where gold/silica Janus particles, coated with a polymerization catalyst on the silica face, exhibited enhanced diffusive motion in a solution of monomers.42 The polymerization reaction occurring on one face of the particle created a concentration gradient of the monomer across the particle surface. The gradient generates an interfacial fluid flow toward higher concentration of monomers (Au face), eventually propelling it with the catalyst end forward (Figure 2). Over longer

varies inversely with the local ionic strength and the gradient of an electrolyte can polarize the counterion cloud around a particle. Such polarization causes ions from the higher solute regions to migrate across the particle toward the other end, generating a fluid flow within the double layer. The particle in consequence, will drift steadily toward the higher solute regions. Particle drift toward higher solute regions, arising only as a result of double layer polarization is known as chemiphoresis. The combination of self-electrophoretic and chemiphoretic effects leads to an overall diffusiophoretic interfacial flow, which powers the movement of particles.37−40 Depending on the nature of the solute added, diffusiophoresis can be classified into two categories: (a) ionic diffusiophoresis, triggered by an electrolyte38 and (b) nonionic diffusiophoresis, triggered by a nonelectrolyte.37 For diffusiophoresis in a monovalent electrolyte, the propulsion speed can be approximated by eq 4.38,39 ⎧ ⎫ ⎪ ⎪ 2 ⎪ ⎪ εζ kBT ⎛ DC − DA ⎞ ε ⎛ kBT ⎞ 2 ⎜ ⎟ ln(1 − ξ ) ⎬ U = ⎨− ⎜ ⎟+ ⎝ e ⎠ 4πη e ⎝ DC + DA ⎠  2πη ⎪    ⎪  ⎪ ⎪ chemiphoresis ⎭ ⎩ electrophoresis d ln C (4) dx

Figure 2. Schematic showing the propulsion mechanism of the polymerization powered motor. Fluid flow from low to high monomer concentration regions causes the motor to move with the catalytic end forward.42 Figure adapted from ref 42 with permission from John Wiley and Sons.

where U is the particle velocity, kB is the Boltzmann constant, T is temperature, η is the viscosity of the solution, e is the charge of an electron, d ln C is the gradient of the electrolyte, DC is the dx diffusion coefficient of the cation, DA is the diffusion coefficient of the anion, ζ is the zeta potential of the particle surface and

time scale, the motion however remains diffusive. Interestingly, there are systems where the inverse mechanism has also been realized. By asymmetric catalysis, the particles generate gradient of product molecules across their surface, which propel them in solution with their noncatalytic end forward.43−45 Powered motion of Pt/Si Janus particles is believed to follow this mechanism. The catalytic Pt side of the motor decomposes hydrogen peroxide into water and oxygen, which leads to the creation of an oxygen gradient across the particle surface, setting it into motion.45 One of the major advantages of powering nanomotors with nonionic self-diffusiophoresis is that it can propel particles in high ionic strength media. Electrolyte diffusiophoresis being dependent on total ion concentration, is not effective in high ionic strength media due to the collapse of interfacial layer on the particle surface. However, in low ionic strength solutions, ionic diffusiophoresis is always more powerful and can result in much higher propulsion speeds than the nonionic counterpart. This is due to the fact that both nonionic diffusiophoresis and chemiphoretic part of ionic diffusiophoresis originates from similar sourcesasymmetries in solute concentrations across the particle surface. Their contributions toward the net propulsion speed is therefore of the same order of magnitude. The additional self-electrophoresis component in ionic diffusiophoresis however augments the propulsion speed making it stronger propulsion mechanisms in low ionic strength conditions (eq 4).

( )

ξ = tanh

eζ 4kBT

From the above discussion, it follows that gradient of an electrolyte imparts motion in colloidal particles independently through two distinct ways. Chemiphoresis arising out of interfacial layer polarization always directs particles toward higher solute concentrations.41 However, the direction of the electrophoretic propulsion depends on the nature of particle’s zeta potential as well as on the relative diffusivities of the ions (DC and DA for cations and anions, respectively) produced as a result of the dissociation of the electrolyte. The resultant particle speed in ionic diffusiophoresis therefore, can be estimated by summing up these contributions. The diffusiophoresis propulsion mechanism can lead to many biomimetic collective emergent patterns, which will be discussed later. Gradient of neutral molecular solutes can also induce propulsion in colloidal particles with specific directionality. Molecules of a nonelectrolyte usually interact with the particle surface with short-range van der Waal’s forces. In nonionic diffusiophoresis, colloidal particles move toward regions of higher or lower solute concentrations depending on the nature of solute-particle interaction. Velocity of a rigid spherical particle in the presence of a nonelectrolyte gradient, which is assumed locally parallel to the particle surface, was quantified by Anderson et al. as37,39 kT dC U = B KL* η dx

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COLLECTIVE DYNAMICS OF SELF-DIFFUSIOPHORETIC MOTORS Many microorganisms in nature use chemical signals derived from each other to communicate and accomplish specific tasks collectively. An example is chemotaxis which involves organisms moving up or down a chemical gradient.46,47 The cells of

(5)

Here, dC is the magnitude of the unperturbed solute gradient, dx L* is a measure of the range of particle-solute interaction. 7668


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Journal of the American Chemical Society Dictyostelium discoideum show robust chemotactic response upon sensing the signaling chemical 3′-5′-cyclic adenosine monophosphate (cAMP). cAMP is secreted when the cells are starved and chemotaxis leads to their aggregation into a migrating slug, which then differentiates into a multicellular fruiting body.48−50 The key aspect of this collective behavior is that these organisms both produce and respond to cAMP trigger for surviving harsh conditions of nutrient depletion. Purely synthetic inorganic systems can also display similar collective dynamics. Micron-sized silver chloride (AgCl) particles dispersed in deionized water collectively move under UV illumination in response to self-generated ion gradients (Figure 3).51

for designing smart nanomachines that can carry out specific tasks collectively in complex environments. There are many possible ways of designing ion-producing nano/microparticles, including particles with attached catalysts or enzymes that form ions as products. These particles should then interact with each other or with inert nano/microparticles through their ionic products. In addition, it allows coordinated and controlled movement of particles that are not attached to each other, which should find wide applicability in targeted material transport and delivery.

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TRANSITIONS BETWEEN COLLECTIVE BEHAVIORS Apart from motility, colonies of microorganisms also display novel transitions between different modes of collective behavior in response to external stimuli. This provides motivation to realize dynamic transitions in synthetic active systems, in order to accomplish different tasks in succession with the same group of multifunctional motors. Dynamic transition in active systems has been demonstrated in AgCl/UV system, when driven by two different chemical reactions. Transition in collective behavior occurs when H2O2 is added to the systemresulting in periodic oscillations of particles.54 Two competing processes are responsible behind the chemical clock. The reduction of AgCl to Ag by UV light and the oxidation of Ag back to AgCl by H2O2 produce and consume HCl, respectively, which leads to periodic reversal of ion gradient. As a result, the AgCl particles exhibit an oscillatory attach−release motion with neighboring silica spheres, as shown in Figure 6(a). Using a reversible chemical reaction, transitions between two modes of collective behavior has been demonstrated in system involving silver orthophosphate (Ag3PO4) microparticles dispersed in dilute ammonia solution. The system reaches equilibrium quickly and any subsequent addition or removal of ammonia shifts the equilibrium, producing or consuming ions that include fast-diffusing OH−. The assembly then transitions between clustering and dispersion (Figure 6b).55 The transition can also occur in response to UV light, and with two orthogonal stimuli, the behavior of the system can be used to design a colloidal logic (NOR) gate (Figure 6c).

Figure 3. Schematic showing photocatalysis of AgCl particles resulting in the formation of H+ and Cl− ions. Higher diffusivity of H+ than that of Cl− generates an electric field to which the nearby particles respond and move with a diffusiophoretic speed Udp. The electric field also influences ions within the double layer of nearby surfaces creating fluid flow with diffusioosmotic speed Udo.51 Figure adapted from ref 51 with permission from Royal Society of Chemistry. With sufficiently high number density, the particles respond to each other’s ion gradients, forming macroscopic schools (shown in Figure 4 below).52

Like Dictyostelium discoideum, each AgCl particle secretes the chemoattractant in the form of H+ and Cl− ions as it moves, to which the other particles respond and modulate their dynamics. This eventually forms “schools” of AgCl particles, mimicking the slime mold’s behavior in two dimensions (Figure 4). An even more interesting dynamic behavior is observed with a mixture of photo activated AgCl particles and silica microspheres dispersed in deionized water. Upon UV illumination, silica spheres respond to the ions secreted by AgCl particles and actively surround them, displaying predator−prey behavior, like that of neutrophils (Figure 5).53 Such long-range emergent interaction in active particle assemblies offers new possibilities

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BUBBLE PROPELLED SYSTEMS Propulsion induced in small scale machines by bubble recoil is another widely investigated mechanism.56−62 Systems with different geometries have been shown to display impressive propulsion speeds following chemically generated bubble recoil. The motion can be controlled using external (e.g., magnetic) fields,63,64 which is ideal for certain applications where motors must reach a destination quickly or move against opposing fluid flows, e.g., blood, with varying speeds and forces. These high speed motors are easy to design and can find useful

Figure 4. Schooling behavior of AgCl particles in deionized water (A) before UV illumination, (B) after 30 s of UV exposure, and (C) after 90 s of UV exposure.52 Figure reproduced from ref 52 with permission from John Wiley and Sons. 7669


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Figure 5. Predator−prey behavior displayed by photoactivated AgCl particles and silica microspheres dispersed in deionized water. Upon UV illumination, AgCl particles are gradually surrounded by silica particles (b and c). Around each AgCl particle an exclusion zone is seen, which disappears when the UV is turned off. The disappearance of exclusion zones is seen in (d). Times in second are indicated in the upper left corners of the images while the status of UV illumination is mentioned in the bottom left.52 Figure reproduced from ref 52 with permission from John Wiley and Sons.

Figure 6. Transition between collective behaviors. (a) Oscillatory attach-release interactions between active silver chloride particles and nearby passive silica spheres due to competing redox reactions;54 (b) silver orthophosphate particles disperse and cluster reversibly with addition and removal of ammonia; (c) The transition from dispersion to clustering in (b) can be halted by UV, and the two different responses of the particles under two orthogonal inputs enable the design of the universal “NOR” logic gate.55 Figures reproduced from refs 54 and 55 with permission from the American Chemical Society.

Figure 7. Catalytic micromotors propelled by asymmetric generation and release of bubbles, demonstrating model applications such as (A) water purification60 and (B) drug delivery.57 Figures reproduced from refs 60 and 57, respectively, with permission from the American Chemical Society.

Figure 8. Diffusion of (A) urease67 and (B) catalase68 increased as a function of increased substrate concentrations (urea and H2O2 respectively). (* indicates a significance value of p < 0.05). (C) Enzyme-functionalized microparticles behave as hybrid autonomous motors in substrate solution.78 Figures adapted from refs 67, 68, and 78, respectively, with permission from the American Chemical Society.

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nonbiological applications such as cargo delivery57 and water purification60 (Figure 7). However, their use in living systems can be limited because of harmful effects of bubbles.

SELF-POWERED MOLECULAR MOTORS Along with the development of all-inorganic and hybrid motile systems, a major incentive has been to design biocompatible 7670


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Figure 9. (A) Schematic of enzyme chemotaxis in Y-shaped microfluidic channel. In the presence of an imposed substrate concentration gradient, active enzymes collectively move toward areas of higher substrate concentrations.68,69 (B) Chemotactic separation of active enzymes from their inactive forms in the presence of imposed substrate concentration gradient.89 Figures adapted from refs 68 and 88, respectively, with permission from the American Chemical Society.

biological systems, the ideal way to power motion in nanoscale systems is though catalysis of chemical reactionsa critical element missing from most work on synthetic molecular systems. Thus, it is important to investigate catalytically powered motion that is compatible with this length scale. Using diffusion NMR spectroscopy, we have examined the behavior of a ruthenium-based Grubbs catalyst during its catalysis of the ring-closing metathesis of diethyldiallylmalonate (DDM).86 As with enzymes, the diffusion of the ∼6 Å radius organometallic catalysts was found to increase with increasing reaction rate. Additionally, the diffusion of the catalyst returned to the base value upon either the addition of an inhibitor or the completion of the reaction. Density functional theory (DFT) calculations were performed to probe the effect of structural changes in the ruthenium complex as a source of the increased diffusion. The conclusion was that the difference between the largest and the smallest form of the catalyst was not significant enough to account for the increased catalyst diffusivity at most substrate concentrations.

active systems powered by biological fuels. Molecules of active enzymes, which catalyze various biomolecular reactions with extraordinary efficiency and specificity, offer excellent model systems to develop smart molecular motors.65 In a series of experiments, we demonstrated that active enzymes, while turning over substrates, generate enough mechanical force to enhance their own diffusion in solution (Figure 8(A,B)).66−69 The diffusive movement of the enzymes increases with increasing reaction rate, following Michaelis−Menten kinetics. In order to account for the observed enhanced diffusion of enzymes during substrate turnover, a number of theoretical proposals have recently been put forward. Propulsion through self-generated diffusiophoretic forces has been suggested for molecules like urease, which generate ionic products during reaction.70 Motility resulting from reaction-induced conformational changes in enzymes has also been proposed as a possibility.71 Bustamante et al. attributed the enhanced diffusion of enzymes to the exothermicity of the chemical reactions involved, where motion is induced via a local thermophoretic effect.72 More recently, Golestanian estimated the magnitude of diffusion enhancement originating from different possible mechanisms and suggested that stochastic swimming due to collective heating and conformational changes are more likely to account for the experimentally measured diffusion enhancement of the enzymes studied thus far.73 Using Langevin/ Brownian dynamics simulations, it was determined that a force of ∼10 pN per turnover was sufficient to cause the enhancement in diffusion of urease and catalase.66−68 These forces are comparable to that produced by myosin, kinesin, and dynein motors (approximately 10 pN),74−76 and within the range necessary to activate integrins,77 biological adhesion molecules responsible for mechanosensing by cells, making force production by enzyme catalysis a potentially novel mechanobiologyrelevant event. Moreover, by tethering active enzymes to larger micronscale particles, Sanchez et al. and we have independently reported enhanced motion of enzyme-powered motors and demonstrated that biocatalytic reactions may be used to power large microscopic objects in solution (Figure 8(C)).78−80 The interesting behavior of self-powered systems at the micro- and nanometer length scales encouraged us to extend our investigation to even smaller active molecular systems. There has been significant work on nanometer-scale synthetic molecular systems, including rotors synthesized by the Feringa,81 nanocars designed by Tour,82 fluctuation driven transport proposed by Astumian,83 and the shuttle systems discovered by Leigh,84 Stoddart85 and others that move molecules along chains. These systems are useful as switches, transport devices, and even as subnanometer pumps. Again, taking a cue from the

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MOLECULAR CHEMOTAXIS In the presence of an imposed substrate concentration gradient, active enzymes collectively move toward areas of higher substrate concentrations, displaying a novel example of molecular chemotaxis (Figure 9A).68,69,87 The collective migration of enzymes toward specific targets promises a variety of applications including sensing, targeted transport, and delivery. The exact mechanism behind enzyme chemotaxis, however, remains an open question. It may involve a Brownian ratchet mechanism arising from substrate-dependent enhanced diffusion.88 As with any nonequilibrium system, a continuous energy input is required for the directional movement, in this case, to maintain the substrate gradient. A second possible mechanism involves the favorable enzyme−substrate interaction. If the enzyme−substrate complex is more stable than the enzyme and the substrate separately, then the enzyme will diffuse to regions of higher substrate concentrations because of the resulting lowering of the chemical potential for the system. Irrespective of the mechanism, however, molecular chemotaxis is stochastic in nature and is different from biological chemotaxis, which requires organisms to have temporal memory of the concentration gradient.48,49 The observation of chemotaxis suggests that, for directed motion, it is not necessary for the active molecule or particle to be asymmetric; one simply needs a gradient in the substrate concentration. The observed chemotactic behavior of single enzymes suggests that for an enzyme that acts on the products of a second, nearby enzymatic reaction might result in its collective 7671


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surface. The negatively charged enzyme molecules bound selectively to the SAM-functionalized gold patterned surface via electrostatic assembly, resulting in an enzyme pattern on the surface (Figure 10(A)). Alternatively, enzymes can also be attached to the gold patch using biotin−streptavidin linkage procedure.91,92 To monitor the fluid flow, sulfate-functionalized polystyrene microspheres were used as tracers. Only in the presence of the substrate, the tracer particles move away from (urease) or toward (catalase, lipase and glucose oxidase) the gold surface, indicating that the surrounding fluid is pumped outward or inward, depending on the specific enzyme pump. The pumping velocity increases with increasing substrate concentration and reaction rate. The fluid flow is driven by a gradient in fluid density generated primarily through changes in the solutal composition, rather than due to reaction exothermicity.91,92 These rechargeable pumps can be triggered by the presence of specific analytes, which enables the design of enzyme-based smart devices capable of acting both as sensors and pumps. Similar pumping can occur in gels incorporating immobilized enzymes in the presence of substrates. For example, gel-bound glucose oxidase pumps insulin out of gel particles when glucose is added to the surrounding solution.90 This research addressed one of the major drawbacks of many synthetic micropumps that are nonbiocompatible and do not interface well with the biological systems. An interesting application of enzyme pumps is in the area of toxin detection where the attenuation in pumping velocity can be related to the concentration of toxins that inhibit the enzymatic reaction.94 Using this principle, sensors for toxic substances, like mercury, cadmium, cyanide and azide, were designed using urease and catalase-powered pumps, respectively, with limits of detection well below the concentrations permitted by the Environmental Protection Agency (EPA) (Figure 10(B)).

movement toward the second enzyme; an example of collective behavior at the molecular level. Thus, catalase was observed to migrate toward glucose oxidase in the presence of glucose since hydrogen peroxide is a product in the oxidation of glucose.68 Importantly, the novel observation of the universality of force production by enzymes and the ability to harness theses forces for directed molecular chemotaxis up a substrate concentration gradient allows the rational design of new technologies for the separation of active enzymes from a complex media. The chemotactic separation of active biomolecules from a mixture has been demonstrated to be sensitive enough to sort out molecules possessing identical physical properties, which cannot otherwise be accomplished using currently known separation techniques (Figure 9(B)).89 In principle, the technique of chemotactic separation can also be used to separate out other active catalysts from their less active or inactive counterparts in the presence of their respective substrates and should, therefore, find wide applicability. We also observed controlled chemotactic propulsion of enzyme-functionalized microscopic particles, a promising step toward developing smart biocompatible payload carriers in complex physiological environments.78

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MOLECULAR PUMPS Enzyme molecules, when immobilized on a surface, transfer the mechanical energy derived from catalysis to the surrounding fluid, resulting in directional fluid pumping. In effect, surfacebound enzymes function as chemically powered machines (Figure 10(A)).90−93 This was demonstrated using four different enzymes as modelscatalase, urease, lipase and glucose oxidase.90 Using e-beam evaporator, gold was patterned on a polyethylene glycol (PEG)-coated glass surface. The patterned surface was functionalized with a quaternary ammonium thiol, which formed a self-assembled monolayer (SAM) on the Au

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LONG RANGE EFFECTS OF MOLECULAR MOTOR SYSTEMS An important aspect of the dynamics of active catalyst particles is their effect on their immediate surroundings. Studies conducted with micron-scale organisms and catalytic particles show that such active assemblies exert considerable influence over the behavior of their surroundings.95−101 Diffusion of inert tracer particles dispersed in a suspension of micron-scale swimmers is dependent upon the total activity of a system; the higher the total activity of the system, the greater the diffusion enhancement of the tracers. Qualitatively, the enhancement was found to be independent of swimming patterns and mechanisms, signifying the generic role of dynamic coupling among the swimmers and their surroundings, which facilitates the distribution of momentum. A key question is whether these effects are also observable at the very low Reynolds number regime (i.e., at the molecular scale). A recent theory predicts that the advection effects induced by active molecular catalysts should also result in significant enhancement of diffusion of passive molecules present in solution.102 Accordingly, we measured the diffusion of molecular tracers, benzene and tetramethylsilane (TMS), in a solution of Grubbs catalyst using diffusion NMR spectroscopy.103 Interestingly, the diffusion of these inert molecules also increased with increasing reaction rate and returned to the respective base values upon the completion of the reaction. The experimental observations demonstrate transfer of momentum from the active catalyst molecules to the surrounding medium, the nature of which is surprisingly similar to the behavior of microscopic active swimmers.

Figure 10. (A) Schematic showing formation of enzyme patterns on PEG coated glass surface and fluid pumping by immobilized enzymes in the presence of substrates.90−93 Figure adapted from ref 90 with permission from the Nature Publishing Group. (B) Inhibitor assay based on enzyme powered micropumps. The presence of inhibitor is detected by monitoring changes in the fluid flow speed, the attenuation of which is directly correlated with the inhibitor concentration.94 Figure reproduced from ref 94 with permission from John Wiley and Sons. 7672


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move faster or longer, little have been done on optimization of the fuel or geometries. Such factors will significantly impact motor speed, fluid drag, fuel consumptions and other factors. In particular, motor systems need to be examined in greater detail in terms of efficiency and compatibility with respect to intended applications.112 The optimization of motor geometries is critically important. Currently, the majority of motors have cylindrical, spherical or screw-like structures. Such geometries may not be best suited for their future intended applications. Motors for in vivo applications have limitations on their shape and size. They must be large enough for directional propulsion while being small and flexible enough to squeeze through narrow capillaries. If the interior of living cells is the intended target, the easiest way to enter is through endocytosis which depends on the size and shape of the motor.12 Thus, far, the focus of motor research has been on the development of motors that move by one dominant propulsion mechanism. However, incorporating orthogonal propulsion mechanisms into a motor offers a greater degree of control. Examples include magneto-acoustic hybrid nanomotors,113 as well as motors that encompass opposing chemical and acoustic propulsion.114 These are the first steps toward the fabrication of true multifunctional motors by incorporating different components for propulsion (multiple fuels), triggered collective behavior (cargo capture/release, schooling/exclusion), and targeting behavior (response to multiple stimuli).112 An important goal is to use motors as micro/nano machines to accomplish what our current tools and instruments cannot. While there have been proof-of-concept applications in recent publications, we have yet to find a niche where motors are indispensable or the technique of choice for a given application. As such, the field is expected to evolve into one with more emphasis on application-based systems. Perhaps the most attractive application for catalytic motors, given the scenario in Fantastic Voyage, is medicine. The immense advantage of targeted motion over diffusion, allowing for the use of less material, is a major incentive for the use of autonomous motors for drug or cargo delivery.112,115−117 Biomedical applications of motors, however, remain relatively unexplored, in part due to the difficulty of motor navigation in vivo. Most studies on motors are conducted in water with low ion content. This is in contrast to biological fluids, which contain a multitude of ions and other components. Blood, for example, is a non-Newtonian viscous fluid that contains plasma, platelets, red and white blood cells that may affect motors’ movement in many different ways. Several additional hurdles remain before practical in vivo applications of motors become a reality. First, the nano/ microtransporters must be derived from biocompatible materials with surfaces appropriately functionalized to promote cell viability. Second, and equally important, is to design selfpowered nano/microbots that can use fuels that are biocompatible, preferably fuels present in the body. Ideally, the nano/ microtransporters will employ enzymes as catalysts and fuels (e.g., glucose) present in living systems.118−120 Third, the transporters need to be powerful enough to move against fluid flows, such as blood flow. Furthermore, the energy transduction mechanism should operate in high ionic medium present in biological fluids. Finally, the most “futuristic” scenario involves the design of populations of synthetic nano and micromotors and pumps that have the ability to organize themselves intelligently, based on signals from each other and from their environment, to perform complex tasks. Particularly attractive

Note that the enthalpy change for the ring-closing metathesis of DDM is approximately +8 kcal/mol (endothermic)86 and therefore cannot contribute to the observed enhanced diffusion of the tracers. The most plausible mechanism involves reactiongenerated advection caused by catalyst molecules “stirring” the solution, which is of great importance especially in intracellular mechanics.104−109 Energy transduction by enzymes at the single molecule and collective level opens up a new area in molecular biophysics. Enzymes, in addition to their primary function as catalysts for biochemical reactions, may have secondary functions as mediators of dynamic interaction pathways. In addition, the possibility of enhanced diffusive transport of molecules by controlled “stirring” in physiological environment has important scientific and technological relevance. The phenomenon could provide new insights into the dynamics of cytoplasmic glass-gel transitions and enhanced mixing in bacterial cells, observed during various metabolic transformations.108 Finally, momentum transfer from freely diffusing active catalysts suggests the possibility that membrane-bound enzymes exert force on cell-membranes, amplifying mechanically induced signaling mechanisms.109

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FANTASTIC VOYAGE External field-driven motion leads to “lock-step” ensemble behavior. To realize the dream of Asimov’s Fantastic Voyage, the bots must be autonomous, harvesting energy from the surroundings and reacting to information at the local level.110 Investigating systems involving molecules and micro/ nanoparticles is inherently challenging due to the stochastic nature of particle dynamics, the limitations of experimental and modeling techniques in characterizing nonequilibrium systems, and need for multidisciplinary expertise.12 Despite the progress in the design of synthetic motors, they cannot carry out complex tasks like their biological counterparts. More integrated functionalities and “division of labor” are two key elements in future design of synthetic motors. The ultimate objective of research in this area is to create a new paradigm for the design of active functional materials and systems by leveraging (a) precise molecular-level control of materials to create functional building blocks, (b) mobility resulting from biomimetic catalytic energy harvesting from the local environment, (c) rapid and reversible assembly capabilities provided by emergent self-assembly, (d) intelligence and communication capabilities found in interacting microorganisms, and (e) ability to perform specific tasks in response to signals from each other and the environment. From a fundamental standpoint, the scientific questions that need to be addressed going forward are (a) What are the possible mechanisms for momentum creation at the microand nanometer length scales and their efficiencies in different environments? (b) Are there optimal motor geometries for sustaining directional motion? (c) How well can motion be directed, preferentially by chemical gradients (i.e., chemotaxis)? (d) What is the nature of interparticle interactions in driven systems? (e) How do the ensemble dynamics of active materials evolve in space-time? and (f) How to we effectively integrate synthetic active molecular assemblies into the biological world? The majority of the motors systems to date have not been optimized. There has only been one study so far on efficiency of artificial motor systems by Wang, Mallouk, and collaborators.111 While the focus of nanomotors has been on the development of new systems and how to make the motors 7673



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are designs that allow coordinated movement of particles with different functionalities that are not attached to each other, making it easier to transport and deliver cargo at specific areas as per requirements. The discovery of particle assemblies that exhibit chemotaxis and predator−prey behavior is a step in this direction. For many future applications, it will be important to have motors that can independently carry out operations such as sensing and reporting, with different populations of interacting motors performing different tasks. The observation that enzymes such as urease, catalase, lipase, DNA polymerase, and others undergo powered movement and pump fluids as they turn over their substrates amends the paradigm that ATP-powered biomotors are a special class of enzymes. This also clearly suggests that (a) single enzyme molecules generate sufficient mechanical force through substrate turnover to cause their own movement and that of the surrounding particles and fluid and (b) the movement becomes directional through the imposition of a gradient in substrate concentration. Indeed, other than the presence of “tracks” that provide directionality, there may not be a significant difference between traditional motor proteins and free swimming enzymes. In addition, it will be interesting to examine the role of membrane-bound enzymes in cell membrane fluctuations. The results described open up a new area of mechanobiology: intrinsic force generation by enzymes and their role in biochemical regulation of cell function. These enzymes can provide sufficient force for the stochastic motion of the cytoplasm and the convective transport of fluid in cells.121 Further, they may be responsible for the observed glass to fluid transition in active bacterial cells.108 The interaction between enzymes in living cells is an area of active research. In many instances, enzymes that participate in reaction cascades have been shown to assemble into metabolons in response to the presence of the initial substrate to facilitate substrate channeling.122−124 The mechanism for metabolon formation, however, remains uncertain in many cases. Metabolon formation through noncovalent interactions has been suggested but rarely demonstrated.125,126 Our observation of preferential migration of enzymes up the substrate gradient suggests that enzymes along a metabolic pathway in which the product of one is the reactant for the next may associate through a process of sequential, directed chemotactic movement.

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Ayusman Sen: 0000-0002-0556-9509 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

We gratefully acknowledge Penn State MRSEC under NSF grant DMR-1420620 and IIT, Gandhinagar for current financial support and Anamika Dey for drawing some of the figures. We thank the students and collaborators who have made possible the results described in this perspective. A.S. also thanks Dr. Suchismita Sen for insightful discussions.

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CONCLUSION Chemically powered micro- and nanoscale motors offer immense potential toward mimicking natural biomolecular systems promising a myriad of novel technological innovations.127 However, the fabrication of tiny, efficient synthetic motors is often associated with scientific and engineering challenges, which need to be tackled with complementary theoretical and experimental approaches. Since the discovery of the first chemically powered system,128 many designs and propulsion mechanisms for autonomous motors have been investigated demonstrating their applications in transport, assembly, and sensing. Freed of usual biological constraints, we now have the unprecedented opportunity to probe the limits of self-organization in these synthetic systems that operate far from equilibrium.129 Thus, it is possible to imagine a day when intelligent machines navigate through the body and perform critical tasks, realizing the functioning of Asimov’s Proteus. 7674


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