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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 by 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 ways to exploit the entire protein scaffold to improve upon the catalytic rate, thereby providing directed evolution with better starting sequences for increasing biocatalytic performance.

Tetrahedral assemblies of stoichiometry M4L6 have been proven to catalyze a range of chemical reactions including the carbon-carbon reductive elimination reaction from transition metals such as gold. Here, we perform quantum chemical calculations of Gold(III) transition metal complexes in vacuum, and encapsulated in Ga4L612- or Si4L68- assemblies within both a reaction field continuum solvent and in an aqueous molecular environment with counterions, to rationalize the rate enhancements observed experimentally for the reductive elimination reaction. We find that the Ga4L612- assembly lowers the energy barrier of the reaction compared to Si4L68-, which is consistent with kinetic trends observed experimentally. We have determined that the primary factor for catalytic rate acceleration stems from the electrostatic environment emanating from the Ga4L612- capsule as opposed to the water or counterions.