De Novo Design of Light-Powered Protein Motor Domains

Abstract

A grand challenge in protein design is the design of molecular machines. These machines integrate energy inputs to undergo cycles of conformational change and perform work at the molecular scale. Such machines are critical in nature–transporting cargo, driving the formation of chemical gradients, and generating tissue-level motions. However, such machines have long been beyond the reach of protein design. Combining challenges in multi-state design with the necessity for energetic inputs and coordination between domains, complex functions are difficult to design for directly. In this work the problem is simplified–designing the motor domains that translate energetic inputs into motion. The design of de novo proteins with large, rigid-body conformational changes is described and functionalization of these protein switches as light-powered motors is detailed. This work establishes both a toolset of components for machine design and methods for generation of additional motor domains with altered characteristics, enabling protein design to approach the capabilities of natural machines and tailor de novo machines to problems not yet addressed by nature.