Enzymes that catalyze the same reaction yet bear no structural resemblance challenge the view that fold dictates function. Here, we probe whether intraprotein electrostatics are a unifying factor in such cases of enzyme catalysis. Focusing on chorismate mutase (CM), a textbook case of electrostatic catalysis found in two structurally unrelated families (AroH and AroQ), we ask (i) whether disparate scaffolds can converge on a common catalytic electric field, and (ii) whether a single reaction can be accelerated by distinct electrostatic fields. Molecular dynamics simulations for six CMs, followed by tensor-based clustering of the three-dimensional electric field (EF), revealed that AroH and AroQ enzymes sample conformations whose active site EFs are nearly identical, eliminating a one-to-one link between tertiary structure and catalytic EF. QM/MM calculations showed a strong linear correlation (R2 > 0.8) between differential substrate–protein electrostatic interaction energy and reaction barrier, demonstrating that the active site EF controls catalytic activity. Nevertheless, enzyme conformations with highly dissimilar fields often displayed indistinguishable barriers, implying multiple electrostatic "solutions" to catalyzing the Claisen rearrangement in CMs. Through statistical analysis of the features of the electron density, distinct field-bond strategies emerged, each reallocating charge along different "electronic lever arms" to selectively stabilize the transition state through electrostatic interactions. Together, the results reframe electrostatic catalysis as a modular design space: a desired EF can be retrofitted onto diverse scaffolds, and concurrently several field-bond blueprints can deliver high catalytic efficiency. This shift from fold-based to field-based design supplies a fresh and transferable vocabulary for data-driven enzyme engineering to access novel chemistry.
Chaturvedi et al. (Tue,) studied this question.