The widespread use of molecular machines in biology has long suggested that great rewards could come from bridging the gap between synthetic molecular systems and the machines of the macroscopic world. In the last two decades, it has proved possible to design synthetic molecular systems with architectures where triggered large amplitude positional changes of submolecular components occur. Perhaps the best way to appreciate the technological potential of controlled molecular-level motion is to recognize that nanomotors and molecular-level machines lie at the heart of every significant biological process. Over billions of years of evolution, nature has not repeatedly chosen this solution for performing complex tasks without good reason. When mankind learns how to build artificial structures that can control and exploit molecular level motion and interface their effects directly with other molecular-level substructures and the outside world, it will potentially impact on every aspect of functional molecule and materials design. An improved understanding of physics and biology will surely follow.

The first steps on the long path to the invention of artificial molecular machines were arguably taken in 1827 when the Scottish botanist Robert Brown observed the haphazard motion of tiny particles under his microscope.1,2 The explanation for Brownian motion, that it is caused by bombardment of the particles by molecules as a consequence of the kinetic theory of matter, was later provided by Einstein, followed by experimental verification by Perrin.3,4 The random thermal motion of molecules and its implications for the laws of thermodynamics in turn inspired Gedankenexperiments (“thought experiments”) that explored the interplay (and apparent paradoxes) of Brownian motion and the Second Law of Thermodynamics. Richard Feynman’s famous 1959 lecture “There’s plenty of room at the bottom” outlined some of the promise that manmade molecular machines might hold.5,6 However, Feynman’s talk came at a time before chemists had the necessary synthetic and analytical tools to make molecular machines. While interest among synthetic chemists began to grow in the 1970s and 1980s, progress accelerated in the 1990s, particularly with the invention of methods to make mechanically interlocked molecular systems (catenanes and rotaxanes) and control and switch the relative positions of their components.7−24

Here, we review triggered large-amplitude motions in molecular structures and the changes in properties these can produce. We concentrate on conformational and configurational changes in wholly covalently bonded molecules and on catenanes and rotaxanes in which switching is brought about by various stimuli (light, electrochemistry, pH, heat, solvent polarity, cation or anion binding, allosteric effects, temperature, reversible covalent bond formation, etc.). Finally, we discuss the latest generations of sophisticated synthetic molecular machine systems in which the controlled motion of subcomponents is used to perform complex tasks, paving the way to applications and the realization of a new era of “molecular nanotechnology”.

1.1. The Language Used To Describe Molecular Machines
Terminology needs to be properly and appropriately defined and these meanings used consistently to effectively convey scientific concepts. Nowhere is the need for accurate scientific language more apparent than in the field of molecular machines. Much of the terminology used to describe molecular-level machines has its origins in observations made by biologists and physicists, and their findings and descriptions have often been misinterpreted and misunderstood by chemists. In 2007 we formalized definitions of some common terms used in the field (e.g., “machine”, “switch”, “motor”, “ratchet”, etc.) so that chemists could use them in a manner consistent with the meanings understood by biologists and physicists who study molecular-level machines.14

The word “machine” implies a mechanical movement that accomplishes a useful task. This Review concentrates on systems where a stimulus triggers the controlled, relatively large amplitude (or directional) motion of one molecular or submolecular component relative to another that can potentially result in a net task being performed. Molecular machines can be further categorized into various classes such as “motors” and “switches” whose behavior differs significantly.14 For example, in a rotaxane-based “switch”, the change in position of a macrocycle on the thread of the rotaxane influences the system only as a function of state. Returning the components of a molecular switch to their original position undoes any work done, and so a switch cannot be used repetitively and progressively to do work. A “motor”, on the other hand, influences a system as a function of trajectory, meaning that when the components of a molecular motor return to their original positions, for example, after a 360° directional rotation, any work that has been done is not undone unless the motor is subsequently rotated by 360° in the reverse direction. This difference in behavior is significant; no “switch-based” molecular machine can be used to progressively perform work in the way that biological motors can, such as those from the kinesin, myosin, and dynein superfamilies, unless the switch is part of a larger ratchet mechanism.14

Artificial Molecular Machines

Chemical methods developed over the past two decades enable preparation of colloidal nanocrystals with uniform size and shape. These Brownian objects readily order into superlattices. Recently, the range of accessible inorganic cores and tunable surface chemistries dramatically increased, expanding the set of nanocrystal arrangements experimentally attainable. In this review, we discuss efforts to create next-generation materials via bottom-up organization of nanocrystals with preprogrammed functionality and self-assembly instructions. This process is often driven by both interparticle interactions and the influence of the assembly environment. The introduction provides the reader with a practical overview of nanocrystal synthesis, self-assembly, and superlattice characterization. We then summarize the theory of nanocrystal interactions and examine fundamental principles governing nanocrystal self-assembly from hard and soft particle perspectives borrowed from the comparatively established fields of micro...

Self-Assembly of Colloidal Nanocrystals: From Intricate Structures to Functional Materials

The photoisomerization of azobenzene has been known for almost 75 years but only recently has this process been widely applied to biological systems. The central challenge of how to productively couple the isomerization process to a large functional change in a biomolecule has been met in a number of instances and it appears that effective photocontrol of a large variety of biomolecules may be possible. This critical review summarizes key properties of azobenzene that enable its use as a photoswitch in biological systems and describes strategies for using azobenzene photoswitches to drive functional changes in peptides, proteins, nucleic acids, lipids, and carbohydrates (192 references).

Azobenzene photoswitches for biomolecules.

Reversible Photocontrol of Biological Systems by the Incorporation of Molecular Photoswitches

Pharmacotherapy is often severely hindered by issues related to poor drug selectivity, including side effects, environmental toxicity, and the emergence of resistance. Lack of selectivity is caused by the inability to control drug activity in time and space. Photopharmacology aims at solving this issue by incorporating photoswitchable groups into the molecular structure of bioactive compounds. These switching units allow for the use of light as an external control element for pharmacological activity, which can be delivered with very high spatiotemporal precision. This Perspective presents the reader with the current state and outlook on photopharmacology. In particular, the principles behind photoregulation of bioactivity, the challenges of molecular design, and the possible therapeutic scenarios are discussed.

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Photopharmacology: Beyond Proof of Principle

Most azobenzene-based photoswitches use UV light for photoisomerization. This can limit their application in biological systems, where UV light can trigger unwanted responses, including cellular apoptosis. We have found that substitution of all four ortho positions with methoxy groups in an amidoazobenzene derivative leads to a substantial (∼35 nm) red shift of the n−π* band of the trans isomer, separating it from the cis n−π* transition. This red shift makes trans-to-cis photoswitching possible using green light (530–560 nm). The cis state is thermally stable with a half-life of ∼2.4 days in the dark in aqueous solution. Reverse (cis-to-trans) photoswitching can be accomplished with blue light (460 nm), so bidirectional photoswitching between thermally stable isomers is possible without using UV light at all.

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Azobenzene Photoswitching without Ultraviolet Light

ConspectusRecently, there has been a great deal of interest in using the photoisomerization of azobenzene compounds to control specific biological targets in vivo. These azo compounds can be used as research tools or, in principle, could act as optically controlled drugs. Such “photopharmaceuticals” offer the prospect of targeted drug action and an unprecedented degree of temporal control.A key feature of azo compounds designed to photoswitch in vivo is the wavelength of light required to cause the photoisomerization. To pass through tissue such as the human hand, wavelengths in the red, far-red, or ideally near infrared region are required. This Account describes our attempts to produce such azo compounds.Introducing electron-donating or push/pull substituents at the para positions delocalizes the azobenzene chromophore and leads to long wavelength absorption but usually also lowers the thermal barrier to interconversion of the isomers. Fast thermal relaxation means it is difficult to produce a large ste...

Red-Shifting Azobenzene Photoswitches for in Vivo Use.

The photoisomerization of azobenzenes provides a general means for the photocontrol of molecular structure and function. For applications in vivo, however, the wavelength of irradiation required for trans-to-cis isomerization of azobenzenes is critical since UV and most visible wavelengths are strongly scattered by cells and tissues. We report here that azobenzene compounds in which all four positions ortho to the azo group are substituted with bulky electron-rich substituents can be effectively isomerized with red light (630–660 nm), a wavelength range that is orders of magnitude more penetrating through tissue than other parts of the visible spectrum. When the ortho substituent is chloro, the compounds also exhibit stability to reduction by glutathione, enabling their use in intracellular environments in vivo.

Photoswitching Azo Compounds in Vivo with Red Light

Longer switching wavelengths and good photochemical yields and stabilities of the cis isomers in reducing aqueous environments are achieved by introducing 2,2'-aminoalkyl substituents into 4,4'-diamido-substituted azobenzenes. The products are thus suitable for photocontrol of biomolecular structures in intracellular environments, such as switching between two peptide configurations (see picture).

Andrew A. Beharry

Papers

Azobenzene photoswitches for biomolecules.

Azobenzene Photoswitching without Ultraviolet Light

Red-Shifting Azobenzene Photoswitches for in Vivo Use.

Photoswitching Azo Compounds in Vivo with Red Light

Spectral tuning of azobenzene photoswitches for biological applications.