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The field of synthetic molecular machines has quickly evolved in recent years, growing from a fundamental curiosity to a highly active field of chemistry. Many different applications are being explored in areas such as catalysis, self-assembled and nanostructured materials, and molecular electronics. Rotary molecular motors hold great promise for achieving dynamic control of molecular functions as well as for powering nanoscale devices. However, for these motors to reach their full potential, many challenges still need to be addressed. In this paper we focus on the design principles of rotary motors featuring a double-bond axle and discuss the major challenges that are ahead of us. Although great progress has been made, further design improvements, for example in terms of efficiency, energy input, and environmental adaptability, will be crucial to fully exploit the opportunities that these rotary motors offer.

Biological molecular machines enable chemical transformations, assembly, replication and motility, but most distinctively drive chemical systems out of-equilibrium to sustain life 1 , 2 . In such processes, nanometre-sized machines produce molecular energy carriers by driving endergonic equilibrium reactions. However, transforming the work performed by artificial nanomachines 3 – 5 into chemical energy remains highly challenging. Here, we report a light-fuelled small-molecule ratchet capable of driving a coupled chemical equilibrium energetically uphill. By bridging two imine 6 – 9 macrocycles with a molecular motor 10 , 11 , the machine forms crossings and consequently adopts several distinct topologies by either a thermal (temporary bond-dissociation) or photochemical (unidirectional rotation) pathway. While the former will relax the machine towards the global energetic minimum, the latter increases the number of crossings in the system above the equilibrium value. Our approach provides a blueprint for coupling continuous mechanical motion performed by a molecular machine with a chemical transformation to reach an out-of-equilibrium state. An artificial molecular machine was designed by coupling a chemical equilibrium to a photoresponsive molecular motor. Upon light illumination, the rotary movement of the motor performs work on the chemical equilibrium generating a far-from-equilibrium state.

The concept of allosteric interaction was initially proposed to account for the inhibitory feedback mechanism mediated by bacterial regulatory enzymes. In contrast with the classical mechanism of competitive, steric, interaction between ligands for a common site, allosteric interactions take place between topographically distinct sites and are mediated by a discrete and reversible conformational change of the protein. The concept was soon extended to membrane receptors for neurotransmitters and shown to apply to the signal transduction process which, in the case of the acetylcholine nicotinic receptor (nAChR), links the ACh binding site to the ion channel. Pharmacological effectors, referred to as allosteric modulators, such as Ca2+ ions and ivermectin, were discovered that enhance the transduction process when they bind to sites distinct from the orthosteric ACh site and the ion channel. The recent X-ray and electron microscopy structures, at atomic resolution, of the resting and active conformations of several homologues of the nAChR, in combination with atomistic molecular dynamics simulations reveal a stepwise quaternary transition in the transduction process with tertiary changes modifying the boundaries between subunits. These interfaces host orthosteric and allosteric modulatory sites which structural organization changes in the course of the transition. The nAChR appears as a typical allosteric machine. The model emerging from these studies has led to the conception and development of several new pharmacological agents. This article is part of a discussion meeting issue ‘Allostery and molecular machines’.

Autonomous molecular machines capable of converting chemical energy into mechanical motion are foundational components for synthetic nanoscale systems. Inspired by biological motors, we report the construction of a tunable, RNA-fueled DNA origami engine that drives the cyclic movement of a 500 nm-diameter particle at the microscale. The engine operates via sequential RNA–DNA hybridization and enzymatic cleavage by RNase H, enabling reversible switching between folded and unfolded conformations without external intervention. By modulating RNA and enzyme concentrations and controlling temperature, we achieve tunable switching kinetics, with transition periods as short as ~10 s. Kinetic modeling reveals that the folding pathway is governed by both productive RNA binding and the enzymatic clearance of misfolded intermediates, while unfolding is primarily controlled by RNase H activity. Since the RNA fuel binds specifically to the DNA strands, each engine is addressable simply by changing the sequences. This work demonstrates a programmable, self-resetting molecular actuator and offers a blueprint for building more complex nanomechanical systems with forces and energies comparable to molecular motors. Molecular machines capable of converting chemical energy into mechanical motion have a range of potential applications. Here, the authors report a tuneable, autonomous DNA origami engine fueled by RNA and activated by RNase H that mimics biological motors, driving cyclic microscale motion creating a self-resetting molecular actuator.

Recent developments in synthetic molecular motors and pumps have sprung from a remarkable confluence of experiment and theory. Synthetic accomplishments have facilitated the ability to design and create molecules, many of them featuring mechanically bonded components, to carry out specific functions in their environment—walking along a polymeric track, unidirectional circling of one ring about another, synthesizing stereoisomers according to an external protocol, or pumping rings onto a long rod-like molecule to form and maintain high-energy, complex, nonequilibrium structures from simpler antecedents. Progress in the theory of nanoscale stochastic thermodynamics, specifically the generalization and extension of the principle of microscopic reversibility to the single-molecule regime, has enhanced the understanding of the design requirements for achieving strong unidirectional motion and high efficiency of these synthetic molecular machines for harnessing energy from external fluctuations to carry out mechanical and/or chemical functions in their environment. A key insight is that the interaction between the fluctuations and the transition state energies plays a central role in determining the steady-state concentrations. Kinetic asymmetry, a requirement for stochastic adaptation, occurs when there is an imbalance in the effect of the fluctuations on the forward and reverse rate constants. Because of strong viscosity, the motions of the machine can be viewed as mechanical equilibrium processes where mechanical resonances are simply impossible but where the probability distributions for the state occupancies and trajectories are very different from those that would be expected at thermodynamic equilibrium.

Many artificial molecular machines have been synthesized, and various functions have been expressed by changing their molecular conformations. However, their structures are still simple compared with those of biomolecular machines, and more energy is required to control them. To design artificial molecular machines with more complex structures and higher functionality, it is necessary to combine molecular machines with simple movements such as components. This means that the motion of individual molecular machines must be precisely controlled and observed in various environments. At the air - water interface, the molecular orientation and conformation can be controlled with little energy as thermal fluctuations. We designed various molecular machines and controlled them using mechanical stimuli at the air - water interface. We also controlled the transfer of forces to the molecular machines in various lipid matrices. In this review, we describe molecular pliers with amphiphilic binaphthyl, molecular paddles with binuclear platinum complexes, and molecular rotors with julolidine and BODIPY that exhibit twisted intramolecular charge transfer.

Hsp104 provides a valuable model for the many essential proteostatic functions performed by the AAA+ superfamily of protein molecular machines. We developed and used a powerful hydrogen exchange mass spectrometry (HX MS) analysis that can provide positionally resolved information on structure, dynamics, and energetics of the Hsp104 molecular machinery, even during functional cycling. HX MS reveals that the ATPase cycle is rate-limited by ADP release from nucleotide-binding domain 1 (NBD1). The middle domain (MD) serves to regulate Hsp104 activity by slowing ADP release. Mutational potentiation accelerates ADP release, thereby increasing ATPase activity. It reduces time in the open state, thereby decreasing substrate protein loss. During active cycling, Hsp104 transits repeatedly betweenwhole hexamer closed and open states. Under diverse conditions, the shift of open/closed balance can lead to premature substrate loss, normal processing, or the generation of a strong pulling force. HX MS exposes the mechanisms of these functions at near-residue resolution.

The design of complex molecular machines and devices represents one of the most ambitious frontiers in nanotechnology, synthetic chemistry, and molecular engineering. These intricate systems, inspired by biological machines, require precise control over atomic and electronic interactions to achieve desired functionalities. Theoretical modeling plays a crucial role in this process, offering predictive insights into molecular behavior, guiding experimental design, and optimizing performance. Methods such as density functional theory, quantum theory of atoms in molecules coupled with widely adopted and distinctive visualization methods, molecular dynamics simulations, and quantum mechanical/molecular mechanical hybrid approaches provide analytical information into the stability in terms of mutual chemical interactions and conformational shaping of flexible supramolecular aggregates for nanotechnological applications. Theoretical approaches also facilitate interdisciplinary integration, bridging chemistry, physics, and materials science to create conceptually hybrid devices with enhanced performance. Machine learning and artificial intelligence are now being incorporated into theoretical modeling, accelerating the discovery and refinement of novel molecular architectures. This fusion of data‐driven approaches with traditional computational chemistry algorithms is expected to revolutionize the design paradigm of soft molecular machines and devices. Theoretical approaches facilitate interdisciplinary integration, bridging chemistry, physics, and materials science to create conceptually hybrid devices with enhanced performance. Machine learning and artificial intelligence are now being incorporated into theoretical modeling, accelerating the discovery of novel molecular architectures. This fusion is expected to revolutionize the design paradigm of soft molecular machines and devices.

The yeast mitochondrial ATP synthase is a rotary molecular machine primarily responsible for the production of energy used to drive cellular processes. The enzyme complex is composed of 17 different subunits grouped into a soluble F1 sector and a membrane-embedded F0 sector. The catalytic head of the F1 sector and the membrane integrated motor module in the F0 sector are connected by two stalks, the F1 central stalk and the F0 peripheral stalk. Proton translocation through the F0 motor module drives the rotation of the subunit 910-ring that generates torque which is transmitted to the calaytic head through the γ subunit of the central stalk. The rotation of the γ subunit causes changes in conformation of the catalytic head which leads to the synthesis of ATP. Biogenesis of the enzyme involves modular assembly of polypeptides of dual genetic origin, the nuclear and the mitochondrial genomes. Most of the yeast ATP synthase subunits are encoded by the genome of the nucleus, translated on cytosolic ribosomes and imported into mitochondria. In the mitochondria, the enzyme forms a dimer which contributes to the formation of cristae, a characteristic of mitochondrial morphology. Substantial progress has recently been made on the elucidation of detailed stucture, function and biogenesis of yeast mitochondrial ATP synthase. The recent availability of high-resolution structure of the complete monomeric form, as well as the atomic model for the dimeric F0 sector, has advanced the understanding of the enzyme complex. This review is intended to provide an overview of current understanding of the molecular structure, catalytic mechanism, subunit import into mitochondria, and the subunit assembly into the enzyme complex. This is important as the yeast mitochondrial ATP synthase may be used as a model for understanding the corresponding enzyme complexes from human and other eukaryotic cells in physiological and diseased states.

This review will focus on micromachines and microrobots, which are objects at the micro-level with similar machine functions, as well as nano-level objects such as molecular machines and nanomachines. The paper will initially review recent examples of molecular machines and microrobots that are not limited to interfaces, noting the diversity of their functions. Next, examples of molecular machines and micromachines/micro-robots functioning at the air-water interface will be discussed. The behaviors of molecular machines are influenced significantly by the specific characteristics of the air-water interface. By placing molecular machines at the air-water interface, the scientific horizon and depth of molecular machine research will increase dramatically. On the other hand, for microrobotics, more practical and advanced systems have been reported, such as the development of microrobots and microswimmers for environmental remediations and biomedical applications. The research currently being conducted on the surface of water may provide significant basic knowledge for future practical uses of molecular machines and microrobots.