Living systems rely on nanoscale molecular “machines”, many of them proteins, to perform a range of essential tasks such as transporting molecular cargo from place to place within cells, causing muscles to contract, and copying genetic information. Developing the ability to build such machines from scratch is a longstanding goal at the interface of biology, physics, chemistry, and engineering. While researchers are now able to synthesize a wide range of complex protein structures, the molecular machines we're currently able to build pale in comparison those used by living systems. The big difference is that while we've largely mastered the ability to synthesize static nanoscale structures, we don't yet know how to build biomolecular machines, structures capable of the complex mechanical motions that power advanced functionality at the nanoscale. This grant funds a project by a team led by David Baker at the University of Washington to create the first artificial protein machines designed from scratch. The team proposes to build rotary molecular motors consisting of self-assembled axle and ring nanostructures that use chemical and/or light energy to perform mechanical work. Baker will attempt to build a nanoscale rotary motor that will be realized via two primary efforts: design of self-assembling axle & ring nanostructures, and the coupling of relative motion (ring about axle) to the consumption of chemical energy by introduction of catalytic sites at the interface between the axle & ring components. Nanoscale imaging, mass spectrometry, and molecular manipulation will be used to verify the designed structures and their functionality. If successful, the project has the potential to launch a new field—de novo design of biomolecular machines—whereby different inputs (chemicals, light, electrical potentials) are coupled to molecular systems to enable mechanical motions that provide a new way to manipulate matter on the atomic scale. Success would also represent a vast improvement in our understanding of nature's biomolecular machines and of the cellular biology they facilitate.