On July 31, 2025, the Defense Advanced Research Projects Agency (DARPA), through its Biological Technologies Office (BTO), released a new program solicitation titled Network of Optimal Dynamic Energy Signatures (NODES). This initiative seeks to unlock a deeper understanding of protein functions by moving beyond static structure-based models and toward dynamic, biophysics-driven simulations. DARPA’s overarching goal is to build a scalable, generalizable capability to predict protein function, which is essential to early bio-threat detection, disease mechanism elucidation, and the rapid development of medical countermeasures (MCMs).
A New Paradigm in Protein Function Prediction
DARPA’s NODES program sets out to build the first biophysics-guided deep learning model that identifies protein function through the observation of dynamic movements, rather than relying solely on sequence or structural homology. The program acknowledges that 90% of the known protein universe remains functionally uncharacterized, often because traditional models fail to account for protein motion and context.
NODES will model folding, binding, and allostery behaviors using high-throughput molecular dynamics (MD) simulations integrated with artificial intelligence (AI) and machine learning (ML) frameworks. The solicitation encourages novel, scalable computational approaches, including ensemble modeling, coarse-graining, and thermodynamic state prediction, with the end goal of producing transferable “MD fingerprints” applicable across protein families.
Program Structure and Technical Requirements
NODES is structured as a 39-month, three-phase program:
- Phase I (12 months): Performers develop and test models predicting protein function across three Functional Areas (FAs):
- FA1: Folding
- FA2: Binding
- FA3: Allostery
This includes two Capability Demonstrations (CDs) using known and unknown protein sequences to benchmark accuracy and performance on DARPA-provided government supercomputers.
- Phase II (15 months): Open only to successful Phase I teams, known as “Super Teams.” This phase focuses on incorporating diverse protein databases and performing stakeholder-driven demos.
- Phase III (12 months): Internal to DARPA and U.S. Government stakeholders.
Teams must be capable of handling million-atom simulations on 100+ GPUs, develop APIs for community access, and prepare for eventual safe public deployment by considering ethical, legal, and societal implications (ELSI).
Key Dates for Proposers
Interested proposers should be aware of several critical deadlines:
- Questions Due: August 15, 2025 (12:00 PM EST) – Deadline for clarification questions.
- Abstracts Due: August 29, 2025 (12:00 PM EST) – Required to be eligible for further participation.
- Full Oral Proposal Package Due: October 7, 2025 – Upon DARPA invitation following abstract review.
Participation in the Proposers’ Day is optional but encouraged, and all proposals must be submitted through DARPA’s Broad Agency Announcement Tool (BAAT) system.
Funding and Award Information
DARPA anticipates making multiple Phase I awards, each funded up to $1.7 million over a 12-month base period under an Other Transaction (OT) for Prototype. There is no cost-sharing requirement for nontraditional defense contractors. Teams that perform well may be eligible to proceed into Phase II and beyond, with Phase II instructions expected around Month 10 of Phase I.
Advancing Human Health and National Biosecurity
The ability to map sequence-to-function at scale has profound implications across biodefense, therapeutics, agriculture, and beyond. By accelerating functional protein discovery, DARPA’s NODES program will help the U.S. rapidly characterize threats, design next-gen pharmaceuticals, and understand disease mechanisms with greater precision.
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