Nature Chemistry, Published online: 05 June 2026; doi:10.1038/s41557-026-02163-0 Proteins sharing a common fold can evolve strikingly different functions, but the underlying energetic logic is often hidden. Now, hydrogen exchange–mass spectrometry reveals conserved energetic ‘blueprints’ that distinguish Venus flytrap transcription factors from transport proteins, uncovering molecular switches for allostery and enabling rational tuning of ligand sensitivity.