Biological and Biomimetic Molecular Machines

REVIEW Biological and biomimetic molecular machines To ny J Hua ng † & The evolution of life facilitates the creation of biological molecular machines. In these so- Bala K Juluri called ‘nanomachines,’ nature elegantly shows that when precisely organized and †Author for correspondence assembled, simple molecular mechanical components can link motions efficiently from the The Pennsylvania State University, Department of nanometer scale to the macroscopic world, and achieve complex functions such as Engineering Science & powering skeletal muscles, synthesizing ATP and producing DNA/RNA. Inspired by nature, Mechanics, University Park, researchers are creating artifical molecular machines with tailored structures and PA 16802, USA Tel.: +1 814 863 4209; properties, with the aim of realizing man-made active nanosystems that operate with the Fax: +1 814 865 9974; same efficiency and complexity as biological nanomachines. It is anticipated that in the Email: [email protected] not-too-distant future, unique applications of biological and biomimetic molecular machines will emerge in areas such as biochemical instrumentation and nanomedicine. A molecular machine (or ‘nanomachine’) is a This review discusses biological molecular mechanical device that is measured in nanome- machines and hybrid systems that integrate these ters (millionths of a millimeter, or units of 10-9 organic nanomachines with inorganic man- meter; on the scale of a single molecule) and con- made devices. Artificial (or ‘biomimetic’) molec- verts chemical, electrical or optical energy to ular machines are then examined, and recent controlled mechanical work [1,2]. The human examples, such as ‘molecular muscles,’ ‘nanocars’ body can be viewed as a complex ensemble of and ‘nanovalves’ for drug delivery, are presented. nanomachines [3,4]. These tiny machines are Finally, the review concludes with a prospective responsible for the directed transport of macro- of developments in nanomachinery. molecules, membranes or chromosomes within the cytoplasm. They play a critical role in virtu- Biological molecular machines ally every biological process (e.g., muscle con- Biological molecular machines are molecular traction, cell division, intracellular transport, proteins that convert the chemical energy ATP production and genomic transcription). released by hydrolysis of ATP into mechanical Even though biological molecular machines energy. Ubiquitous in biological systems, these have a long history, the idea of constructing arti- nanomachines are responsible for the directed ficial molecular machines is recent. In 1959, transport of macromolecules, membranes or Richard Feynman originated the idea of artificial chromosomes within the cytoplasm, thus play- molecular machines in his historic address to the ing a critical role in cell behavior and architec- American Physical Society, ‘There is Plenty of ture [3,4,6–8]. Over the past decade, interest in Room at the Bottom’ [5]. The soon-to-be Nobel biological molecular machines has blossomed. laureate contemplated, “What are the possibili- Atomic structures of various nanomachines have ties of constructing molecular-scale mechanical been solved by X-ray crystallography, new machines … What would be the utility of such molecular machines have been discovered, and machines? Who knows? I cannot see exactly forces, steps and speeds have been measured at what would happen, but I can hardly doubt that the molecular level. In nanotechnology, two when we have some control of the arrangement main fabrication approaches have been utilized. of things on a molecular scale we will get an In the bottom-up approach, materials and enormously greater range of possible properties devices are built from some of the smallest that substances can have, and of the different building blocks, atoms or molecules. In the ‘top- Keywords: biomimetic, things we can do.” In the early 1980s, the earliest down’ approach, nano-objects are constructed bistable rotaxanes, bottom-up fabrication, molecular examples of synthetic molecular-level machines from larger entities using etching and deposi- machines, nanotechnology were reported; these were based on the photoi- tion techniques. Recently, hybrid devices inte- somerization of azobenzene [6]. Since then, grating ‘bottom-up’-based biological molecular part of research in the field of artificial molecular machines and top-down-based inorganic nanos- machines has accelerated. tructures have been realized. These scientific 10.2217/17435889.3.1.107 © 2008 Future Medicine Ltd ISSN 1743-5889 Nanomedicine (2008) 3(1), 107–124 107 REVIEW – Huang & Juluri breakthroughs have not only led to a much- functional differences between kinesin and improved understanding of cell motility, but myosin. Conventional kinesin operates alone or in also have a profound impact in the field of small numbers to transport membrane-bound nanoscience and nanotechnology. organelles over large distances (up to a millimeter) along microtubules, whereas muscle myosin oper- Myosin & kinesin ates in huge arrays of up to a billion molecules in a Myosin, kinesin and their relatives are linear large muscle fiber and moves relatively short dis- motors that convert the energy of ATP hydroly- tances (up to approximately one micron) along sis into mechanical work along polymer actin filaments (Figure 2) [12,13]. Myosin provides substrates – myosin along actin filaments in the power for all of our voluntary motions (e.g., muscles and cells, and kinesin along microtu- running, walking and lifting) as well as for invol- bules (Figure 1) [9,10]. In a kinesin molecule, two untary motions (e.g., beating of the heart). heads, each about 8 nm long, are joined at the Recent years have witnessed a strong interest in coiled-coil neck. The neck then connects to a the exploration of kinesin-based biological molec- long-coiled coil that terminates in the tail, region ular machines for nano- and microscale locomo- and binds to the organelle cargo. Myosin's heads tion applications. Limberis and Stewart are approximately twice the size of kinesin’s and demonstrated that kinesin could be engineered are composed of two major domains: the motor and used to transport silicon microchips along domain which binds to actin and nucleotides, microtubules [14]. Negatively charged microtu- and the regulatory domain, which is an 8-nm- bules bound electrostatically to a positively long α-helix stabilized by two calmodulin-like charged coverslip were aligned in a microfluidic light chains. A long-coiled-coil rod connects to channel. Next, genetically modified kinesin the regulatory domain and oligomerizes to form motors attached with silicon microchips were the thick filament in muscle. added into the microfluidic channel. The micro- The developments in DNA/RNA sequences chips were observed to move in a variety of ways have helped reveal the similarities between myosin (Figure 3), depending on how they were bound to and kinesin [11]. The core 180 amino acids within microtubules. If a microchip moved along parallel the myosin and kinesin head structures have the microtubules, it traveled along linearly at a maxi- same fold. Furthermore, the preserved sequence mum speed of 0.8 µm/s (Figure 3A). When it inter- direction and order of the α-helices and β-sheets acted with antiparallel microtubules, it rotated within the core suggest that these two biomotors (Figure 3B). A microchip with one end fixed flipped evolved from a common ancestor. Yet, despite over (Figure 3C). This work proved that kinesin these structural similarities, there are profound motors had enough force to transport cargos that are much larger than kinesin molecules, thus pav- Figure 1. Schematic drawing of ing the way for future development of biomotor- two kinesin motors bound to a based nanosystems. microtubule segment. To improve the efficiency of kinesin-based nanosystems, the orientation of microtubules must be controlled and aligned. Hiratsuka et al. developed a lithographic process to restrict microtubules onto fabricated tracks and control the direction of kinesin’s mechanical motion [15]. The experiment used two concentric circles with arrowhead patterns facing opposite directions (Fig- ure 4). Without the arrowheads in the pattern, the microtubules would travel either clockwise or counterclockwise in either circle. However, once the arrowheads pattern was added, within a few The microtubule is built up from tubulin dimers and minutes the microtubules would travel in the has a diameter of 24 nm. Each kinesin motor same direction that the arrows pointed towards. molecule has two motor domains or heads which As microtubules enter the arrowhead from the are connected by a neck region and a long stalk. correct direction, they could easily pass through; The total length of the kinesin molecule is however, if microtubules entered from the reverse approximately 80 nm [13]. direction, they would usually bump against the Reproduced with permission from [13]. wall at the base of the arrow and turn around. 108 Nanomedicine (2008) 3(1) futurefuture sciencescience groupgroup Biological and biomimetic molecular machines – REVIEW Figure 2. Myosin filament operation. The sliding of myosin along actin filaments causes muscle contraction and extension. Four different versions of the arrowhead pattern the alignment of magnetic nanoparticle func- were tested; the most efficient pattern had a 73% tionalized microtubules in magnetic fields (Figure chance of reversing microtubules in the wrong 5) [16]. In this study, microtubules

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