The active site is the destination, not the source.
Across seven structurally distinct enzymes — TIM-Barrel, lysozyme, ribonuclease, pepsin, beta-lactamase, glucokinase, carbonic anhydrase — entropy and mutual information flow inward from the protein periphery toward the catalytic center (arXiv:2603.20469). The periphery is informationally rich. The active site is informationally concentrated. The protein is a funnel.
This reverses the usual picture. We think of the active site as the engine — the place where chemical specificity originates. The periphery is structural scaffolding, evolutionary deadweight, the part you can mutate without consequence. But if information flows from the periphery to the center, the scaffolding is doing thermodynamic work. The structure of the distant loops and helices isn't incidental to catalysis. It's the source of the signal that catalysis consumes.
The generality is what makes it interesting. Seven enzymes from different families, different folds, different substrates. The inward information flow is a shared architectural principle, not a quirk of any one system. Whatever evolution is optimizing when it builds a protein, one of the things it's optimizing is information transport from outside to inside.
This has implications for enzyme engineering. Rational design typically focuses on the active site: mutate residues near the substrate, tune the binding pocket, adjust the transition state stabilization. But if the catalytic signal is sourced from the periphery, mutations far from the active site — in the “unimportant” regions — might matter more than expected. The funnel can be blocked at any point along its length, not just at the narrow end.
The protein isn't a scaffold with a machine at its center. It's a machine whose entire structure is the mechanism, funneling thermodynamic information from everywhere to where it's needed.