Significance All known terrestrial protein enzymes fold robustly and explore the complex energy landscapes that are required for activity. The catalytic residues must be held together in precise positions that may conflict with the correct folding dynamics of the domain itself. We quantified these energetic conflicts and found that these are effectively present in extant enzymes, regardless of the protein oligomeric state, overall topology, and enzymatic class. The conservation of these energetic signatures is higher than the conservation quantified in the primary structures.