Davari_2022_ChemSusChem__

Biocatalysis in organic solvents (OSs) enables more efficient routes to the synthesis of various valuable chemicals. However, OSs often reduce enzymatic activity which limits the use enzymes in OSs. 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 substituting aromatic to polar residue(s) hold great potential to highly improve OSs resistance. Hence, surface polar engineering enable to be a powerful and general strategy for generating OS-tolerant lipases and other enzymes, thereby adapting the catalyst to the desired reaction and process with OSs.