Although the ubiquitous role that long-ranged electric fields play in catalysis has been recognized, it is seldom used as a primary design parameter in the discovery of new catalytic materials. Here we illustrate how electric fields have been used to computationally optimize biocatalytic performance of a synthetic enzyme, and how they could be used as a unifying descriptor for catalytic design across a range of homogeneous and heterogeneous catalysts. While focusing on electrostatic environmental effects may open new routes toward the rational optimization of efficient catalysts, much more predictive capacity is required of theoretical methods to have a transformative impact in their computational design-and thus experimental relevance-when using electric field alignments in the reactive centres of complex catalytic systems.

We review the standard model for de novo computational design of enzymes, which primarily focuses on the development of an active site geometry composed of protein functional groups in orientations optimized to stabilize the transition state for a novel chemical reaction not found in nature. Its emphasis is placed on the structure and energetics of the active site embedded in an accommodating protein that serves as a physical support that shields the reaction chemistry from solvent, which is typically improved upon using laboratory directed evolution. We also provide a review of design strategies that move beyond the standard model, by placing more emphasis on the designed enzyme as a whole catalytic construct. Starting with complete de novo enzyme design examples, we consider additional design factors such as entropy of individual residues, correlated motion between side chains (mutual information), dynamical correlations of the enzyme motions that could aid the reaction, reorganization energy, and electric fields as a way to exploit the entire protein scaffold to improve upon the catalytic rate, thereby providing directed evolution with better starting sequences for increasing the biocatalytic performance.

We report the effect of conformational dynamics on the fluctuations of electric fields in the active site of the enzyme Ketosteroid Isomerase (KSI). While KSI is considered rigid with little conformational variation to support different stages of the catalytic cycle, we show that KSI utilizes cooperative side chain motions of the entire protein scaffold outside the active site, which contribute negligibly to the electric fields on the substrate, by progressively stabilizing electric field contributions by particular active site residues at different timescales. The design of synthetic enzymes could benefit from strategies that can take advantage of the dynamics by using electric fields fluctuations as a guide.