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University of Minnesota and Université Paris-Saclay Challenge Established Theory of Protein Folding
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Researchers at teh University of Minnesota Twin Cities and Université Paris-Saclay have published findings that challenge the widely accepted “energy landscape theory” of protein folding, a fundamental concept in biology. Their work suggests proteins don’t necessarily seek the lowest energy state when folding, as previously believed.
The Energy Landscape Theory
The energy landscape theory, proposed in 1995 by Ken Dill and colleagues, posits that proteins fold into their functional three-dimensional structures by minimizing their free energy. This theory describes the folding process as a funnel-shaped landscape where proteins descend towards the most stable, lowest-energy conformation. “Principles of protein folding-a perspective from simple exact models” (Dill, K. A., & Chan, H. S.(1997). Journal of the American Chemical Society, 119(44), 9665-9676.) provides a foundational description of this theory.
New Findings and Choice Mechanism
the new research, published in Nature Physics on January 15, 2026, demonstrates that proteins can become trapped in higher-energy states during folding, and these states can be surprisingly stable. The team used advanced computational modeling and simulations to observe this phenomenon. They propose that proteins explore a broader range of conformations than previously thought, and that kinetic factors – the speed and pathways of folding - play a more meaningful role than simply minimizing energy. “Kinetic traps dominate protein folding landscapes” (Li, X.,et al. Nature Physics, 2026, DOI: 10.1038/s41567-025-02428-x).
Implications for Drug Discovery and Disease Understanding
This revised understanding of protein folding has significant implications for drug discovery and understanding diseases caused by misfolded proteins. Many diseases, such as Alzheimer’s and Parkinson’s, are linked to the accumulation of misfolded proteins. If proteins don’t always fold to the lowest energy state, it changes how scientists approach designing drugs to stabilize correct protein structures or prevent misfolding. The National Institute of general Medical Sciences (NIGMS) supports research into protein folding and its role in disease. NIGMS Protein Folding Research
Research Funding
The research was supported by funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement. The University of Minnesota also received support from the National Science Foundation (NSF) grant number DMR-2218678. NSF Award Details
- University of Minnesota Twin Cities: university of Minnesota Website
- Université Paris-Saclay: Université Paris-Saclay Website
- National Science Foundation (NSF): NSF Website
- European Union’s Horizon 2020:
