Review Cite This: Chem. Rev. 2020, 120, 288−309 pubs.acs.org/CR Synthetic Systems Powered by Biological Molecular Motors Gadiel Saper and Henry Hess* Department of Biomedical Engineering, Columbia University, New York, New York 10027, United States ABSTRACT: Biological molecular motors (or biomolecular motors for short) are nature’s solution to the efficient conversion of chemical energy to mechanical movement. In biological systems, these fascinating molecules are responsible for movement of molecules, organelles, cells, and whole animals. In engineered systems, these motors can potentially be used to power actuators and engines, shuttle cargo to sensors, and enable new computing paradigms. Here, we review the progress in the past decade in the integration of biomolecular motors into hybrid nanosystems. After briefly introducing the motor proteins kinesin and myosin and their associated cytoskeletal filaments, we review recent work aiming for the integration of these biomolecular motors into actuators, sensors, and computing devices. In some systems, the creation of mechanical work and the processing of information become intertwined at the molecular scale, creating a fascinating type of “active matter”. We discuss efforts to optimize biomolecular motor performance, construct new motors combining artificial and biological components, and contrast biomolecular motors with current artificial molecular motors. A recurrent theme in the work of the past decade was the induction and utilization of collective behavior between motile systems powered by biomolecular motors, and we discuss these advances. The exertion of external control over the motile structures powered by biomolecular motors has remained a topic of many studies describing exciting progress. Finally, we review the current limitations and challenges for the construction of hybrid systems powered by biomolecular motors and try to ascertain if there are theoretical performance limits. Engineering with biomolecular motors has the potential to yield commercially viable devices, but it also sharpens our understanding of the design problems solved by evolution in nature. This increased understanding is valuable for synthetic biology and potentially also for medicine. CONTENTS 9. Outlook 300 Author Information 300 1. Introduction 288 Corresponding Author 300 2. Biomolecular Motors: A Brief Introduction 289 ORCID 300 2.1. Biomolecular Motors 289 Notes 300 2.2. Kinesin-1 and Dynein 289 Biographies 300 2.3. Myosin II 290 Acknowledgments 300 3. Linear Biomolecular Motors Applications 290 References 300 Downloaded via COLUMBIA UNIV on April 6, 2020 at 13:58:36 (UTC). 3.1. Actuators 291 3.2. Sensors 291 3.3. Computation 292 4. Rotary Biomolecular Motor Applications 293 1. INTRODUCTION See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. 5. Optimizing Molecular Motors for Nanodevices: From Biomolecular to Artificial Motors and Motor proteins are biological molecular motors responsible for energy conversion and movement from the molecular to the Applications 293 1−5 5.1. Improving the Quality of Biomolecular macroscopic scale in many organisms. The F1-ATPase is Motor Preparations 293 used in biology as a generator, where the rotary motion of the stalk subunit driven by the F0 portion of the F0F1-ATPase 5.2. Hybrid Motors Built with Artificial and 6,7 Biomolecular Motors Components 294 complex is used to produce ATP, but the hydrolysis of ATP 5.3. Artificial Motors 294 can also drive rotary motion. DNA polymerase and RNA 6. Collective Effects and Their Applications 295 polymerase replicate DNA and transcribe genes by generating linear movement.8,9 Myosins use the hydrolysis of ATP to 6.1. Collective Motion of Filaments 295 fi 6.2. Dynamic Self-Organization of Biomolecular exert forces on actin laments and are involved in many cellular processes, including muscle contraction, cell division, Motors 296 ffi 10,11 6.3. Macroscopic Motion Driven by Molecular cargo tra cking, and cell signaling. Kinesins and dynein Motors 297 7. Control of Motion Driven by Biomolecular Special Issue: Molecular Motors Motors 297 Received: April 22, 2019 8. Limitations and Challenges 298 Published: September 11, 2019 © 2019 American Chemical Society 288 DOI: 10.1021/acs.chemrev.9b00249 Chem. Rev. 2020, 120, 288−309 Chemical Reviews Review hydrolyze ATP to “walk” along microtubules and participate in possible ways to overcome them. We will conclude with our − intracellular cargo transport and cell division.12 14 outlook on the future of the field. Our understanding of motor proteins is highly detailed due to their large biological and medical significance which has 2. BIOMOLECULAR MOTORS: A BRIEF engendered an extensive research effort from the biomedical INTRODUCTION ff community. For example, their structures in di erent 2.1. Biomolecular Motors conformational states have been determined with X-ray 15−23 Biomolecular motors are proteins that are responsible for crystallography, their biological roles were elucidated 2,4,5 with biochemical and biophysical methods,24,25 and the mechanical movement in biology. Motors that generate development of single molecule methods enabled new insights linear movement include members of the kinesin and myosin into the coupling of mechanical and chemical events during the protein families, dynein, DNA polymerase, and RNA polymer- − operation of the motor.26 30 This detailed understanding ase, and are for example responsible for muscle contraction and inspired scientists and engineers at the end of the last fast anterograde transport in neurons (Figure 1). Motors that millennium to utilize motor proteins as “off-the-shelf” components in hybrid nanosystems and devise unique applications utilizing these biological molecular motors as − force-producing units.31 35 We have reviewed the progress over the first decade of this effort in 2009,36 and we now aim to provide an update of the progress in the field in the past decade. Three fundamentally different approaches aim to produce active movement in engineered nanosystems: active nano- and microelectromechanical systems (NEMS/MEMS), artificial molecular motors, and biological molecular motors. NEMS/ MEMS-based motors convert electricity to mechanical work.37 They are built from artificial materials, such as silicon, polymers, or carbon nanotubes, and have in principle advantages with regard to stability over protein-based − structures.38 40 However, these motors are generally larger, less efficient, require a dry environment to prevent stiction, and are less compatible with medical applications than biomo- lecular motors. Artificial molecular motors are produced using the methods of synthetic organic chemistry and use ingenious molecular mechanisms to convert light or chemical energy to mechanical work.41 These motors have made tremendous Figure 1. Schematic illustrations of biomolecular motors. (a) DNA polymerase synthesizing DNA. (b) The F0F1-ATPase complex in a progress in recent years, recognized by the 2016 Nobel Prize in membrane, that utilizes the chemical potential of proton gradient to Chemistry to Feringa, Sauvage, and Stoddart,42 and have been 43 convert ADP to ATP, contains the rotary motor F1-ATPase. (c) In used to fabricate contractile polymer gels as well as drill holes muscle, thick filaments assemble from myosin II motors and move 44 into cell membranes to facilitate drug delivery. However, along actin filaments, where troponin together with tropomyosin these motors are synthesized in milligram quantities at the regulates access to binding sites for the motors. (d) Kinesin and laboratory scale and a scale-up of the complex synthesis is dynein move along microtubules, for example, within axons of rather challenging. Biological molecular motors, or biomolec- neurons. Adapted with permission from ref 34. Copyright 2018 ular motors for short, are optimized by billions of years of American Chemical Society. evolution and achieve energy conversion efficiencies of over 40%.45,46 As proteins they are good candidates for biomedical 47,48 can generate rotary movement include F1-ATPase, which is applications and are easy to produce in bacteria and cells. “ ” Furthermore, because biology can be considered to be a proof used in cells as a generator where the rotary movement of the of the feasibility of nanotechnology,49 the study of central stalk unit driven by the F0 subunit is used to catalyze the synthesis of ATP,52 and the flagellar motor, which is biomolecular motors provides both inspiration and a tool 53 chest.50,51 responsible for the movement of bacteria and sperm. Most of Here, we briefly introduce biomolecular motors and then the engineering applications use the linear motors kinesin-1 review the efforts over the past decade to utilize these motors and myosin II, and occasionally dynein. Therefore, we will in engineered systems and devices, including biosensors, focus on these motors. Polymerases generate forces, but the complexity of the actuators, biocomputers, switches, logic gates, screen pixels, ffi 54 and active matter. We will discuss efforts to improve the process make it di cult to exploit in an engineering context. ff Rotary movement driven by F1-ATPase has attracted great available biomolecular motors and also e orts to design new 55 motors incorporating biological building blocks, such as DNA attention in the past, but less work has been done in the past decade. The flagellar motor is difficult to isolate, but hybrid strands or enzymes. We review the work aiming at inducing fl and utilizing