Enzyme reactions, quantum chemical study

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

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. 

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. 

Knowledge about the enzyme structure is usually a prerequisite to set up a quantum chemical model and investigate the reaction mechanism. However, there are cases where the energetic feasibility of reaction mechanisms can be evaluated by studying individual steps without information about the structures. One example is the study of pyruvate-form ate lyase (PFL), where the calculations were able to support one of the suggested mechanisms before the X-ray crystal structure was solved." Another example is the study of the reaction mechanism of spore-photoproduct lyase (SPL), for which the crystal structure still remains to be solved. ... 

In this chapter, we have discussed how enzyme active sites and reaction mechanisms can he studied using quantum chemical models. The usefulness of this approach has been validated for a large number of enzymes during the last decade. Here, we have presented three recent examples concerned with the reactivity of epoxides in different enzymes. 

Excited-states simulations were mainly limited to small and medium-sized molecules before the 90s. However, many important photophysical processes, as for example, the photoisomerization of rhodopsin, take place in a biological environment, seldom not without the presence of an enzyme. To study photochemical processes in the large-size systems, alternative methods are required. One such method, the QM/MM method," was developed by Warshel and Levitt in 1976. This approach combines the accuracy of quantum chemical models with the speed of molecular mechanics. An alternative method to combine different quantum chemical approaches, the ONIOM method, was developed by Morokuma and co-workers." These methods were initially used in the context of ground-state reactions. Early applications of the QM/MM hybrid method to photochemical processes can be found as early as 1982," however, it was not until at the beginning of this century that the method started to be used extensively for photochemical and photophysical dynamics. To find representative investigations of that time consult the reference list." " ... 

A cytochrome P450-catalyzed Friedel-Crafts reaction is proposed in the biosynthesis of viridicatumtoxin (225, Scheme 45). ° The transformation involves a spirocyclization of the geranyl-substituted substrate (226). This biosynthetic chemistry is notable as the first terpene cyclization catalyzed by a P450 enzyme (VrtK). It suggests a mechanism with oxidation to the allyl cation (227), with subsequent ring formation, hydride shift, and Friedel-Crafts cyclization steps. The proposed mechanism was further studied by quantum chemical calculations. 

The forcefields discussed in Section 2.1 use energy functions which do not take into account quantum effects. Many important processes are intrinsically quantum mechanical, and thus cannot be modelled classically. SA has been used in con-juction with density functional theory, the Schrodinger equation, chemical reaction dynamics, electronic structure studies, and to optimize linear and nonlinear parameters in trial wave functions. This is important because quantum effects are often embedded in an essentially classical system. This has motivated mixing the classical fields with the quantum potentials in simulations known as quantum mechanic/molecular mechanic hybrids. Including quantum effects is important in the study of enzyme reactions, and proton and electron transport studies. 

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