Modeling Enzymatic Enantioselectivity using Quantum Chemical Methodology

Abstract

The computational study of enantioselective reactions is a challenging task that requires high accuracy, as very small energy differences have to be reproduced. Quantum chemical methods, most commonly density functional theory, are today an important tool in this pursuit. This Perspective describes recent efforts in modeling asymmetric reactions in enzymes by means of the quantum chemical cluster approach. The methodology is described briefly and a number of illustrative case studies performed recently at our laboratory are presented. The reviewed enzymes are limonene epoxide hydrolase, soluble epoxide hydrolase, arylmalonate decarboxylase, phenolic acid decarboxylase, benzoylformate decarboxylase, secondary alcohol dehydrogenase, acyl transferase, and norcoclaurine synthase. The challenges encountered in each example are discussed, and the modeling lessons learned are highlighted.

Mechanisms of metal-dependent non-redox decarboxylases from quantum chemical calculations

“…With this size it has been possible to solve a large number of diverse mechanistic problems. The size has also been shown to be sufficient to represent the chiral environment of the active site, making the approach a useful tool in the investigation of enzymatic enantioselectivity [47] .…”

“…To this end, quantum chemical calculations have become a very important tool in this endeavor. In particular, the so-called cluster approach has been successfully used to study the mechanisms and selectivities of a wide range of enzymes [47] , [48] , [49] , [50] , [51] , [52] , [53] .…”

“…First, however, we will briefly describe the adopted computational methodology without going into much technical details. The interested reader is referred to some of the recent reviews on the topic [47] , [48] , [49] , [50] , [51] , [52] , [53] .…”

Mechanism and Chemoselectivity for HOCl‐Mediated Oxidation of Zinc‐Bound Thiolates

“…HOCl‐sensing is conserved across representative CZB domains, [7] indicating that the mechanism is localized at the conserved 3His/1Cys Zn 2+ core. Therefore, we designed a model system for computational analyses from the crystal structure of the core CZB domain in E coli diguanylate cyclase Z solved at 2.20 Å resolution (DgcZ, PDB ID: 3 t9o, Figure 1b) [27] . The C α −C β bond of each zinc‐ligated residue was cut, and the C β replaced with methyl groups, resulting in a cationic [Zn(MeS)(Im) 3 ] + complex 1 optimized to a structure with Zn−S and Zn−N bond lengths consistent with the crystal structure (Figure 1c).…”

The Effects of the Metal Ion Substitution into the Active Site of Metalloenzymes: A Theoretical Insight on Some Selected Cases

“…Quantum mechanical electronic structure methods based on the density functional theory (DFT) were used to simulate the reactions catalyzed by metalloenzymes in the framework of quantum mechanics (QM) cluster approximation. This methodology was largely validated as a viable approach to explore enzymatic mechanisms and to give insights on the catalytic processes [28][29][30][31][32][33][34][35]. Moreover, the cluster modelling simulations represent a well-consolidated strategy to model transition states and to identify chemical mechanisms in calculations on small models of enzyme active sites as evidenced by the literature, [28,29,33,35] providing also detailed and fundamental chemical insights into metal-complex geometries and electronic structures [31][32][33][34][35][36][37].…”