Authors
Qiu, J., Tang, G., Feng, T., Zheng, B., Liu, Y., Zheng, P.
Abstract
The rational design of proteins that maintain structural integrity under concurrent thermal, mechanical, and chemical stress remains a central challenge in molecular engineering. We present a hierarchical framework that transforms a fragile -helical domain into an ultrastable scaffold by integrating AI-guided design with foundational chemical principles. This approach progresses from global architectural reinforcement, using multiple AI tools to create a stabilized four-helix bundle, to local chemical tuning, where AlphaFold3 guides the installation of salt bridges and metal-coordination motifs. A computational pipeline leveraging physics-based screening such as molecular dynamics (MD) simulations efficiently distilled millions of designs into a minimal candidate set. The resulting proteins exhibit unprecedented multi-axis stability, with mechanical unfolding forces exceeding 200 pN, thermal resilience >100 {degrees}C, and high resistance to chemical denaturants. By systematically dissecting the contributions of hydrophobic packing, electrostatics, and metal coordination, we establish a general blueprint for imparting extreme robustness. This work bridges AI-driven structural generation with chemical precision, advancing the creation of durable proteins for mechanistic studies and synthetic biology.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Nov 2025.
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