The U.S. National Science Foundation’s Directorate for Technology, Innovation and Partnerships (TIP) is charged with accelerating use-inspired and translational research and development (R&D) to advance U.S. competitiveness in key technology focus areas.

The Use-Inspired Acceleration of Protein Design (USPRD) initiative will accelerate the translation of novel approaches to protein design and enable new applications of importance to the U.S. bioeconomy.

Significant advances have been made in the ability of researchers to predict the three-dimensional (3D) structure of proteins from primary sequence, and to use that information to design proteins with desired characteristics. These advances have been enabled by: macromolecular modeling; training data available in repositories such as the Protein Data Bank (PDB); the application of artificial intelligence (AI) and machine learning; and high-throughput protein characterization. The improved accuracy of in-silico design has reduced the number of constructs that need to be validated in costly and time-consuming “wet lab” experiments.

USPRD aims to advance protein design and its applications to the next level by:

A. Accelerating the use of protein design technologies to enable applications beyond human therapeutics, e.g., applications to advanced materials, biomanufacturing, agriculture and food security, environmental remediation, sustainability, and climate-related challenges.

B. Extending the range of accurate prediction models to enable the design of enzymes and families of enzymes. This will require models and tools that account for the dynamic nature of protein structures.

USPRD seeks significant breakthroughs in the application of protein design through:

a) Use-driven activities that design novel proteins with specific characteristics and demonstrate their application, e.g., the design and characterization of specific enzymes or enzyme families that promote sustainability by degrading specific bio-contaminants.

b) Infrastructure components, such as software tools, datasets, and characterization services that can readily be accessed by protein designers.

c) Designer-facing components that will ensure the accessibility of the infrastructure components and collaboration with protein designers engaged in the third-party use-driven activities.

d) Ecosystem components, such as standards and roadmaps, that help coordinate the actions of multiple parties within the emerging ecosystem. This may also include open-source software and/or data repositories.

e) Workforce components focused on the training of translational talent with the skills and passion to engage in use-driven protein design activities.

USPRD will use the Ideas Lab process (see PAPPG Chapter II.F.6), starting with an intensive meeting that brings together multiple diverse perspectives. A key aim of this Ideas Lab workshop will be to identify an aggressive (but attainable) set of use-driven activities together with the infrastructure component breakthroughs, designer-facing components, and ecosystem components required to realize them.

USPRD includes two tracks:

Track I. Use-driven application for small binders.

Track II. The design and use of enzymes and families of enzymes.