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Structure-guided Design Rules for Advancing Biocatalysis through Long-term Enzyme Stability

Project description

Engineered enzymes for sustainable chemical manufacturing

Enzymes carry out chemical reactions with remarkable precision, offering significant sustainability advantages over conventional chemical processes in industrial chemistry. However, enzymes are fragile outside their natural environment, losing activity under harsh conditions required for industrial applications such as high temperatures, organic solvents and prolonged reaction times. This mismatch limits their broader adoption. With the support of the Marie Skłodowska-Curie Actions programme, the STABLE project aims to develop a framework for engineering more stable enzymes. The approach will combine systematic experimental profiling with computational modelling and molecular dynamics simulations. By identifying rules for enzyme stabilisation, the project will accelerate the development of robust biocatalysts for sustainable pharmaceutical and industrial chemical manufacturing.

Objective

Biocatalysis has emerged as a key technology for sustainable chemistry, enabling the use of enzymes that are highly selective and active under mild conditions for the synthesis of pharmaceutical and industrially relevant products. However, despite these advantages, enzyme stability remains a major issue, particularly under harsh, non-natural conditions, such as high substrate loadings, elevated temperatures, prolonged reaction times, and the use of organic solvents, which are essential for solubilizing hydrophobic substrates or simplifying product recovery. This mismatch between natural function and industrial requirements is the core bottleneck preventing biocatalysis from competing with established techniques, such as metal catalysis and fermentation.

Unlike traditional metal catalysts, enzymes can be altered and tuned through protein engineering. Directed evolution has delivered remarkable success, yet it remains resource-intensive and often produces variants optimized only for narrow operational conditions. To rationally engineer more stable enzymes, we must first understand their mechanisms of deactivation. Many predictive tools for stability screening are already established, including FoldX, FireProt, and FuncLib. While powerful, these tools rarely generalize across enzyme classes or predict long-term functional performance. Highlighting the need to integrate dynamic aspects when studying and to identify transferable features for predictive engineering.

STABLE aims to establish transferable design rules for enhancing enzyme operational stability in organic co-solvent systems. We propose a combined wet- and dry-lab approach that combines systematic experimental stability profiling with computational modelling, pattern recognition, and dynamic insights from molecular dynamic simulation. The main objective is to develop a protein-structure-centric decision framework for the predictive engineering of robust biocatalysis for sustainable chemical manufacturing.

Fields of science (EuroSciVoc)

Keywords

Programme(s)

Topic(s)

Funding Scheme

HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

(opens in new window) HORIZON-MSCA-2025-PF

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Coordinator

TECHNISCHE UNIVERSITAT BERLIN
Net EU contribution
€ 202 125,12
Address
STRASSE DES 17 JUNI 135
10623 Berlin
Germany
Region
Berlin Berlin Berlin
Activity type
Higher or Secondary Education Establishments
Links
Total cost
No data