Polar substitutions on the surface of a lipase substantially improve tolerance in organic solvents
Dr. Haiyang Cui, Markus Vedder, Prof. Dr. Lingling Zhang, Prof. Dr. Karl-Erich Jaeger, Prof. Dr. Ulrich Schwaneberg*, Dr. Mehdi D. Davari*, ChemSusChem, doi.org/10.1002/cssc.202102551
Surface polar engineering is a powerful strategy to generate OS-tolerant lipases and other enzymes
Biocatalysis in organic (co-)solvents (OSs) provides numerous industrially attractive advantages, e.g. the favorable shift of reaction equilibria, increased solubility of substrate/product, alternation of substrate specificity and enantioselectivity, suppression of water-dependent side reactions and easy product recovery. As such, enzymatic reactions conducted in OSs would enable to combine the synthetic power of enzymes with chemical synthesis efficiently in industrial and pharmaceutical fields. However, OSs frequently lead to a dramatic drop in enzymes’ catalytic activity and even deactivation. Herein, we report a comprehensive understanding of interactions between surface polar substitutions and DMSO by integrating the molecular dynamics (MD) simulations of 45 variants from Bacillus subtilis lipase A (BSLA) and substitution landscape in “BSLA-SSM” library. By systematically analyzing 39 structural-, solvation-, and interaction energy-based observables, we discovered hydration shell maintenance, DMSO reduction, and decreased local flexibility simultaneously govern the stability of polar variants in OS. Moreover, the fingerprints of 1644 polar-related variants in three OSs demonstrated that substituting aromatic to polar residue(s) hold great potential to highly improve OSs resistance. Hence, surface polar engineering is a powerful strategy to generate OS-tolerant lipases and other enzymes, thereby adapting the catalyst to the desired reaction and process with OSs. In addition, the decryption of the molecular principles, which lead to the enzyme resistance in OSs, brings substantial knowledge to guide protein engineering campaigns and promote biocatalysis in OSs.
Dr. Haiyang Cui, PhD student (2016-2020) in Prof. Dr. Schwaneberg’ group, was financially supported by the China Scholarship Council (CSC) scholarship. This work was realized in the division Computational Biology and was supported by computing resources granted by JARA-HPC from RWTH Aachen University (JARA0169 and JARA0187).
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Cui, H., Vedder, M., Zhang, L., Jaeger, K. E. Schwaneberg, U, & D. Davari, M. Polar substitutions on the surface of a lipase substantially improve tolerance in organic solvents. ChemSusChem. https://doi.org/10.1002/cssc.202102551
Figure. Investigating the molecular dynamics (MD) simulations of 45 variants from Bacillus subtilis lipase A (BSLA) and 1644 substitutions’ landscape in “BSLA-SSM” library obtained a comprehensive molecular understanding of interactions between surface polar substitutions and DMSO.