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Protein enzymes have shown great potential in numerous technological applications. However, the design of supporting materials is needed to preserve protein functionality outside their native environment. Direct enzyme-polymer self-assembly offers a promising alternative to immobilize proteins in an aqueous solution, achieving higher control of their stability and enzymatic activity in industrial applications. Herein, we propose a modeling-based design to engineering hydrogels of cytochrome P450 and of PETase with styrene/2-vinylpyridine (2VP) random copolymers. By tuning the copolymer fraction of polar groups and of charged groups via quaternization of 2VP for coassembly with cytochrome P450 and via sulfonation of styrene for coassembly with PETase, we provide quantitative guidelines to select either a protein-polymer hydrogel structure or a single-protein encapsulation. The results highlight that, regardless of the protein surface domains, the presence of polar interactions and hydration effects promote the formation of a more elongated enzyme-polymer complex, suggesting a membrane-like coassembly. On the other hand, the effectiveness of a single-protein encapsulation is reached by decreasing the fraction of polar groups and by increasing the charge fraction up to 15%. Our computational analysis demonstrates that the enzyme-polymer assemblies are first promoted by the hydrophobic interactions which lead the protein nonpolar residues to achieve the maximum coverage and to play the role of the most robust contact points. The mechanisms of coassembly are unveiled in the light of both protein and polymer physical-chemistry, providing bioconjugate phase diagrams for the optimal material design.