Catalytic Principles from Natural Enzymes and Translational Design Strategies for Synthetic Catalysts

Abstract

As biocatalysts, enzymes are characterized by their high catalytic efficiency and strong specificity but are relatively fragile by requiring narrow and specific reactive conditions for activity. Synthetic catalysts offer an opportunity for more chemical versatility operating over a wider range of conditions but currently do not reach the remarkable performance of natural enzymes. Here we consider some new design strategies based on the contributions of nonlocal electric fields and thermodynamic fluctuations to both improve the catalytic step and turnover for rate acceleration in arbitrary synthetic catalysts through bioinspired studies of natural enzymes. With a focus on the enzyme as a whole catalytic construct, we illustrate the translational impact of natural enzyme principles to synthetic enzymes, supramolecular capsules, and electrocatalytic surfaces.

Figure 1

Relationship between C=O vibrational frequency and the corresponding electrostatic field calibrated by a solvatochromic model. (a) FTIR spectra of C=O in p-Ac-Phe (black), [p-Ac-Phe]RNase S (blue), and [p-Ac-Phe]S-peptide (red). (b) The calibration of the free p-Ac-Phe with different applied electric fields. Dotted blue and red lines present the experimental data of peak frequencies of the probe placed in the two protein constructs. (c) MD simulated results with the average values illustrated by solid lines that correlate well with the calibration measurement in (b). Permission is obtained from ref (24). Copyright (2013) American Chemical Society.

Figure 2

Ketosteroid Isomerase (KSI). (a) KSI with inhibitor 19-NT in the active site (PDB: 5KP4); (b) active site and reaction mechanism that starts the two-step acid/base process; (c) Electric field projections by KSI residue onto carbonyl bond of 19-NT, using molecular dynamic simulations with a polarizable force field. The electric field is the sum of the direct field (from permanent electrostatics) and the induced filed (from the induced dipole term). ∼ 90% of the total electric field comes from the three main active site residues: Asp-40 (−15.85 MV/cm), Tyr-16 (−44.47 MV/cm), and Asp-103 (−37.75 MV/cm). Permission is obtained from ref (4). Copyright (2019) American Chemical Society.

Figure 3

Electrostatic free energy guided mutations of KE15 (R1) and all improved mutants predicted (R2-R5) from electrostatic calculations using eq 1. (a) Location of the four mutations of KE15 best variant. (b) Electrostatic free energy stabilization diagram of KE15 and all improved mutants predicted from eq 1 for both RS and TS. There is moderate ground state destabilization going from R1 to R2 and R4 to R5, but most of the free energy improvements reported come from transition state stabilization that directly improves the catalytic step. Permission is obtained from ref (43). Copyright (2018) American Chemical Society.

Figure 4

Ga₄L₆^12– supramolecular catalyst for reductive elimination from gold complexes. (a) Structure of Ga₄L₆^12– and the proposed reaction mechanism.^,, (b) The gold complex, the reactive Au–C₁ and Au–C₂ bonds, and the complexed water molecule position in the transition state; the nanocage and greater water environment are not shown for clarity. (c) The activation free energy stabilization by region using eq 1 for the complexed water molecule, the nanocage, and the remaining water solvent obtained by ensemble-averaged MD calculations.

Figure 5

Electric fields for ketosteroid isomerase (KSI) for both the bound and unbound states between active site residues Tyr-16 and Asp-103 and the 19-NT inhibitor. (a) O–O distance between oxygen atoms in Tyr-16 and Asp-103 to carbonyl oxygen of 19-NT inhibitor in the bound state (the structure is illustrated in Figure 2). (b) The cross-correlation between the total electric field from KSI (black) and the electric fields from Tyr-16 (red) and Asp-103 (green) in the bound state as a function of time. (c) A statistical fluctuation gives rise to a broken hydrogen bond between Asp-103 and NT-19, that (d) reduces the correlation (and magnitude) of the electric field from Asp-103. With permission from ref (4). Copyright (2019) American Chemical Society.

Figure 6

Representative configuration showing the mixture of chemisorbed and physisorbed CO molecules (circled in green) at the last 2.0 ps time point of the AIMD simulation for CO binding to Ag(111) for B97M-rV. The statistical data is collected after 500 fs’s pre-equilibration for the 2 ps trajectories.