DE novo design and engineering of biological error correction
Active Project Grant Awarded Last action
- Award ID
- DP1EB038939
- Recipient
-
The Regents Of The University Of California. San Francisco UEI KMH5K9V7S518
- Awarding agency
-
National Institute of Biomedical Imaging and Bioenginering
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,296,000
Award facts
- Assistance listing
- 93.310 Trans-NIH Research Support
- Completion date 24% complete
- Funding agency
- Office of the Director National Institutes of Health, Department of Health and Human Services
- Place of performance
- San Francisco, CA 94143, USA
Award details come from USAspending.gov.
Description
- Abstract
- Biological systems have evolved a remarkable ability of error correction in processes essential for life. Non- equilibrium mechanisms of kinetic proofreading increase the fidelity (correct versus incorrect outcomes) by several orders of magnitude, beyond that expected solely from differences in equilibrium binding to correct versus incorrect binding partners. Yet we are not harnessing this amplification of specificity in applications of biological engineering. The central challenge and goal of this proposal is to pioneer approaches to engineer mechanisms of biological error correction from the ground up that can be integrated generally into engineered systems - for therapeutic purposes or biotechnology - to increase the fidelity of molecular recognition by 2-4 orders of magnitude. Natural error correction systems are complex, incompletely understood, and difficult to manipulate. Here we will instead build generalizable systems DE novo with proteins that are computationally engineered to be tunable, controllable, and composable. Based on recent breakthroughs, including from our laboratory, in the precision, accuracy, and complexity of DE novo designed protein structures, functions, and dynamics guided by deep learning, we posit that such a transformative advance might now be within reach. We propose conceptual innovations in DE novo protein design beyond the state of the field by engineering energy- driven multi-step pathways that implement kinetic proofreading DE novo to achieve error correction rivaling that of natural systems. Specifically, we will conceptualize, build, and test generalizable computational approaches to couple mechanisms of protein recognition, modification, conformational change, kinetically controlled assembly, molecular event cascades, and energy consumption. We will build multiple instances of each protein part, molecular function, and system-level behavior, with designed variation in quantitative parameters including rates and affinities. Using in vitro reconstituted multi-protein systems, high-throughput quantitative assays, and modular engineering of cells, we will assess molecular and system-level function using systematic and precise targeted perturbation and parameter sweeps that will be integrated with and inform predictive modeling. Overall, this ambitious plan will lay the foundation for groundbreaking new abilities to correct biological errors and amplify specificity in engineered systems, enabling future advances across discovery science, biomedical applications, and biotechnology.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $1,148,000 | |
| Original award | $1,148,000 |
Quick answers
Who received award DP1EB038939?
DP1EB038939 was awarded to The Regents Of The University Of California. San Francisco by National Institute of Biomedical Imaging and Bioenginering (National Institutes of Health) on August 15, 2025.
How much is award DP1EB038939 worth?
$2,296,000 has been obligated on DP1EB038939.
Which agency awarded DP1EB038939?
National Institute of Biomedical Imaging and Bioenginering (National Institutes of Health) awarded DP1EB038939, with funding from Office of the Director (National Institutes of Health).
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