In spite of excellent properties of supercritical CO2 in enzyme catalyzed reactions, destabilizing effects of CO2 molecules on the enzyme structure limits the industrial applications of this green solvent in the field of biocatalysis. Here, based on the substantial role of charged surface residues such as lysines in enzyme inactivation, we introduced for the first time, Post Translational Modifications (PTMs), a famous concept in molecular biology, as a protein stabilization strategy in supercritical condition. Lysine groups were modified using PTM templates to find out more about the exact mechanism of enzyme inactivation in supercritical CO2 and to explore a new way for protein stabilization in this solvent. We used MD simulation as common tool for in situ examining enzyme structure in supercritical fluids, for the investigation of structural consequence of modifications. Different modifications including acetylation, methylation, phosphorylation, and carboxylation have been applied on the model enzyme. For comparison to CALB structure in supercritical CO2, the acetylated enzyme was also simulated in aqueous solvent at 300 and 353 K. Interestingly, acetylation of lysine residues prevents enzyme from denaturation at high temperatures in water, which is in agreement with experimental observation in aqueous solution. However, acetylation is not so useful for stabilization of enzyme in supercritical CO2. In contrast, methylation and carboxylation efficiently stabilize enzyme in supercritical CO2. Phosphate groups in phosphorylated lysines destabilize enzyme by formation of excess hydrogen bonds by inappropriate groups and perturb enzyme conformation. Moreover, it was found that modification of surface arginine residues was not so satisfactory in stabilization of the enzyme. This finding supports the mechanism of lipase inactivation through direct interaction of CO2 molecules on lysine residues and formation of carbamates. We think this new exploration can open new window for developing enzyme catalyzed mechanism of enzyme inactivation in scCO(2). (C) 2016 Elsevier B.V. All rights reserved.