Enzyme reactions, quantum chemical

Szefczyk B, Mulholland AJ, Ranaghan KE, Sokalski WA (2004) Differential transition-state stabilization in enzyme catalysis Quantum chemical analysis of interactions in the chorismate mutase reaction and prediction of the optimal catalytic field. J Am Chem Soc 126 16148—16159... 

In QSAR of enzyme inhibition reactions, quantum-chemically calculated electrostatic or MO-related descriptors have been widely used. The former are expected to describe the complex formation between enzyme and the substrate, whereas the latter reflect the chemical reactivity of the substrate at the site. Already in 1967, Klopman and Hudson [83] developed a polyelectronic perturbation theory, according to which the drug-receptor interactions can be under either charge or orbital control. Thus the net atomic... 

The reaction mechanisms and regioselectivities of sEH, LEH, and HheC were analyzed in detail. The computational results support the proposed mechanisms and are able to explain the experimentally observed regioselectivities of these enzymes. The quantum chemical approach also allowed us to identify and quantify the importance of individual functional groups for the reaction mechanism and the regioselectivity of epoxide opening. 

Aqvist J and A Warshel 1993. Simulation of Enzyme Reactions Using Valence Bond Force Fields a Other Hybrid Quantum/Classical Approaches. Chemical Reviews 93 2523-2544. 

J. R. Alvarez-Idaboy, R. Gonzalez-Jonte, A. Hernandez-Laguna, Y. G. Smeyers, Reaction Mechanism of the Acyl-Enzyme Formation in /3-Lactam Hydrolysis by Means of Quantum Chemical Modeling , J. Mol. Struct. 2000, 204, 13 - 28. 

Transition metal sulfide units occur in minerals in nature and play an important role in the catalytic activity of enzymes such as hydrogenase and nitrogenase. Industrial processes use transition metal sulfides in hydroprocessing catalysis. Both the metal and the sulfur sites in these compounds can undergo redox reactions which are an important part of their reactivity. Thus, the electronic situation of the ReS4 anion and related complexes is of considerable interest and has been evaluated applying quantum chemical methods. 

III. The Cluster Model Approach to Quantum Chemical Studies of Enzyme Reactions... 

A reaction looked at earlier simulates borate inhibition of serine proteinases.33 Resorufin acetate (234) is proposed as an attractive substrate to use with chymotrypsin since the absorbance of the product is several times more intense than that formed when the more usual p-nitrophcnyl acetate is used as a substrate. The steady-state values are the same for the two substrates, which is expected if the slow deacylation step involves a common intermediate. Experiments show that the acetate can bind to chymotrypsin other than at the active site.210 Brownian dynamics simulations of the encounter kinetics between the active site of an acetylcholinesterase and a charged substrate together with ah initio quantum chemical calculations using the 3-21G set to probe the transformation of the Michaelis complex into a covalently bound tetrahedral intermediate have been carried out.211 The Glu 199 residue located near the enzyme active triad boosts acetylcholinesterase activity by increasing the encounter rate due to the favourable modification of the electric field inside the enzyme and by stabilization of the TS for the first chemical step of catalysis.211... 

Quantum chemical methods aim to treat the fundamental quantum mechanics of electronic structure, and so can be used to model chemical reactions. Such quantum chemical methods are more flexible and more generally applicable than molecular mechanics methods, and so are often preferable and can be easier to apply. The major problem with electronic structure calculations on enzymes is presented by the very large computational resources required, which significantly limits the size of the system that can be treated. To overcome this problem, small models of enzyme active sites can be studied in isolation (and perhaps with an approximate model of solvation). Alternatively, a quantum chemical treatment of the enzyme active site can be combined with a molecular mechanics description of the protein and solvent environment the QM/MM approach. Both will be described below. 

Quantum Chemical Approaches to Modelling Enzyme Reactions Cluster (or Supermolecule) Approaches... 

Both examples also illustrate the state-of-the-art methodology used in molecular modeling of enzymatic reactions. Due to the size of enzymes quantum-chemical theory levels cannot be currently applied to whole systems. As the remedy for this situation the system is usually divided into at least two zones. The smaller one includes reactants and catalytically important fragments of the enzyme and is treated at the quantum level. The remaining part, which usually consists of the remaining part of the enzyme and water molecules, is treated at the molecular mechanics level. This so called QM/MM approach, suffers from many conceptual pitfalls,3-6 but still has proved to be highly successful in studying mechanisms of enzymatic reactions. 

To provide a flavor of how computational chemistry has been applied to biochemical problems, this chapter focuses on a small subset of computational biochemistry, namely, computational enzymology. Presented here are some examples of how quantum chemical computations have been used to understand the mechanism of catalysis provided by enzymes. The chapter ends with a look at one of the true holy grails of biochemistry the abihty to design an enzyme for a specific purpose, to catalyze a particular reaction where nature provides no such option. 

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