Local Electric Fields: From Enzyme Catalysis to Synthetic Catalyst Design

Abstract

This Mini-Review Article outlines recent advances in the study of local electric field (LEF) governed enzyme catalysis and the application of the LEF principle in synthetic catalyst design. We start by discussing the electrostatics principles that drive enzyme catalysis, and its experimental verifications through vibrational Stark spectroscopy. Subsequently, we describe aspects of LEFs other than catalysis, i.e., induction of mechanistic crossovers, among others. Here, we focus on the early work done using computational tools, along with some recent contributions. Following an in-depth discussion of the role of LEFs in enzyme catalysis, we then highlight some recent works on designed local electric fields (D-LEF) and their applications in organic synthesis. Subsequently, we turn to D-LEFs in synthetic enzymes and supramolecular systems (cf. the work by the Head-Gordon group). We end by discussing some of the software packages that have been developed to analyze local electric fields computationally. Overall, the present Mini-Review Article paints an insightful picture of the current state of the art using LEF in enzyme catalysis and its application for further bioengineering and synthetic organic frameworks in a broad perspective.

Evaluating the Transition State Stabilization/Destabilization Effects of the Electric Fields from Scaffold Residues by a QM/MM Approach

“…In addition to its active site, an enzyme includes a protein scaffold that consists of the majority of enzyme residues. The protein scaffold not only plays key roles in the substrate/cofactor binding and substance transportation − but also is vital to the boost of catalytic efficiency of the enzyme via the electrostatic stabilization effect. − Especially, the scaffold residues are shown to contribute to the preorganized electric field in the active site of natural enzymes, which can stabilize the charge distribution of the transition state (TS) more than that of the reactant state (RS), leading to acceleration of the catalytic rate. ,− In contrast to natural enzymes that can optimize their protein scaffold through billions of years of evolution, the design of de novo enzymes mainly focuses on the active site, while the scaffolds of the de novo enzymes may lack sufficient electrostatic preorganization as in natural enzymes, which limits the catalytic efficiency of the de novo enzymes. , Accordingly, systematic evaluation of the TS stabilization (or destabilization) effects of the electric fields generated by the scaffold residues is key to both understanding the emergence of the eminent catalytic activity of natural enzymes and the rational design of de novo enzymes.…”

Can an external electric field switch between ethylene formation and l-arginine hydroxylation in the ethylene forming enzyme?

“…46 Several computational and experimental reports have proposed that the IntEF of an enzyme provides a preorganized polar environment that stabilizes the transition state (TS) during enzyme catalysis and influences the mechanistic crossover in several enzymes and small molecule reactions. 31,32,47–51…”

“…19 Along these lines, multiple studies have predicted the importance of electrostatic effects in enzyme catalysis. [28][29][30][31][32][33][34][35][36][37] Extending this notion, Shaik and co-workers have even utilized external electric fields (ExtEF) on several small model complexes and enzymes to improve their reaction efficiencies and selectivities. [38][39][40][41][42] A computational study predicted that an ExtEF applied along the reaction axis of Diels-Alder reactions can catalyze/ inhibit the rate and control its endo/exo selectivity; 43 this prediction was validated by Coote and colleagues in an experimental setup.…”

“…46 Several computational and experimental reports have proposed that the IntEF of an enzyme provides a preorganized polar environment that stabilizes the transition state (TS) during enzyme catalysis and influences the mechanistic crossover in several enzymes and small molecule reactions. 31,32,[47][48][49][50][51] In this study, we show that the IntEF along the Fe-O bond of EFE is predicted to differ between the 2OG/L-Arg binding modes that favor ethylene generation or L-Arg hydroxylation reactions. We indicate that by applying an ExtEF along the Fe-O bond in the EFEÁFe(III)ÁOO À Á2OGÁL-Arg complex (Fig.…”

Toward Metal- and Catalyst-free Reactions: Deciphering the substituent and external electric field effects on the Diels-Alder reaction between Ethylene and Nitrosoethylene

“…In this scenario, the existence of an external electric eld (EEF), properly oriented, has the potential to further stabilize or destabilize these charge transfer contributors and thus in uence the energy [12,[20][21][22] . Meir et al (2010) explored by theoretical means the effect of targeted EEFs on the rate, mechanism and endo/exo selectivity of DA reactions between butadiene and ethylene and cyclopentadiene and maleic anhydride.…”