ONIOM QM/MM approach

The present chapter reviews applications in biocatalysis of the ONIOM method. The focus is on studies performed in our research group, in most cases using the two-layer ONIOM(QM MM) approach as implemented in Gaussian [23], The studied systems include methane monooxygenase (MMO), ribonucleotide reductase (RNR) [24, 25], isopenicillin N synthase (IPNS) [26], mammalian Glutathione peroxidase (GPx) [27,28], Bi2-dependent methylmalonyl-CoA mutase [29] and PLP-dependent P-lyase [30], These systems will be described in more detail in the following sections. ONIOM applications to enzymatic systems performed by other research groups will be only briefly described. 

Theoretical studies that has investigated the homolysis step in different enzymatic systems [68-70] reveal that small models comprising only the corrin ring and two ligands are insufficient and that inclusion of more amino acids are essential to stabilize the radical intermediates. Recently, a QM/MM study of the initial phase of the glutamate mutase-catalyzed reaction found a large electrostatic stabilization by the surrounding protein [70], In our study of MCM we employed the ONIOM QM MM approach to reveal the role of the protein in the rupture of the Co—C5 bond [29],... 

Some of the above mentioned studies also use two-layer ONIOM QM MM approaches to include the full protein in an MM description. Other examples of QM MM calculations of metal enzymes include heme oxygenase [89], nitrate reductase [90] and peptide deformylase [91]. Finally, we note that the ONIOM (I IF Amber) potential energy surface has been directly used in a molecular dynamics study (ONIOM/MD) of cytidine deaminase [92],... 

The 3-layer combination, ONIOM(QM QM MM), shown in Figure 2-1, is also a unique combination not available in the generic QM/MM approach and we recommend this method strongly, as the border between QM and MM regions is pretty far away form the active part of the system and the effects of scaling is... 

If MM is chosen as the low level method in ONIOM, the approach falls into the general class of the QM/MM strategies (see refs [21,22] and references cited therein). However, in most of the QM/MM approaches, one calculation is run a QM method is applied to the core of the system and the rest (usually the largest part) is treated by a force field that contains intramolecular and intermolecular potential energy terms in the form of analytic functions. The interaction of the MM environment with the QM chromophore is represented by the hamiltonian term. 7/yM/MM will include the... 

Despite their relatively recent appearance in 1995, the IMOMM and ONIOM methods have been extremely productive when applied to transition metal chemistry [15]. A substantial amount of publications have been concerned with homogeneous catalysis, and they will be reviewed in this contribution. Other applications to transition metal chemistry, in structure [16, 17] and reactivity [18, 19], will not be treated here. Methodological aspects of the QM/MM approach, in connection with its application to transition metal chemistry, have been reviewed in a number of papers [20-22]. 

Rega et al. [104] have proposed the QM/MM approach ADMP/ONIOM which implements the atom-centred density matrix propagation within the QM/MM ONIOM scheme of Maseras and Morokuma [105]. The ONIOM approach consists of separating the system in parts described at different levels of theory, for example a model part treated at Hartree-Fock or DFT level (QM), embedded in surroundings that will be treated at a molecular mechanics level (MM). The real system is composed of the model system and of the surrounding system, and the ONIOM energy is ... 

Due to their importance for research but also for industrial chemistry, transition metal based catalysts are intensively investigated. Ananikov et al. [684] reviewed various appUcatimis of hybrid ONIOM methods within this field. This review involves reaction mechanisms and enantioselective reactions of transition metal complexes, e.g. Ti-catalyzed cyanation of benzaldehyde [685], Cu-catalyzed cyclopropanation [686], Mn-porphyrin catalyzed epoxidation of alkene [687], and Mo-catalyzed nitrogen activation [688]. These approaches involve QM/QM as well as QM/MM approaches. 

ONIOM based approaches employing QM/QM or QM/MM schemes were used to describe the vibrational spectra of some molecules of biological interest [841] and of boldine hydrochloride [842], Further examples of the computation of vibrational spectra with QM/MM approaches are reviewed in recent overviews of Barone and co-worker [541, 544], A description of state-of-the-art modeling of IR spectra to elucidate secondary-structure information of peptides and proteins is provided by Amadei et al. [843, 844],... 

Sato presents an alternative method to both continuum solvation models and hybrid QM/MM or ONIOM approaches. This is represented by the reference interaction site model (RISM) formalism when combined to a QM description of the solute to give the RISM-SCF theory. 

The ONIOM approach (our Own N-layer Integrated molecular Orbital molecular Mechanics) developed by the Morokuma group takes an alternative approach to hybrid QM/MM. The distinct advantages of the ONIOM approach are that... 

The ONIOM method, as implemented in the Gaussian03 program package [73], has been proven to be applicable to large molecular systems, where different levels of theory are applied on various parts of the molecular cluster [74,75]. The interactions of non-nucleoside RT inhibitors with the amino acids of the inhibition pocket of the enzyme, and the induced conformational changes, are the results of several sensitive phenomena which need careful and accurate treatment. Calculations of the whole complex, however, is rather difficult because of the large size of the system. Therefore, an approach combining QM/MM or ONIOM methods for such HIV-1... 

The dummy junction atom or link atom approach introduces so-called link atoms to satisfy the valence of the atoms on the QM side of the QM/MM interface. Usually this atom is a hydrogen, but other atom types have also been used, e.g. halogens such as fluorine or chlorine. The link atom method can be used with both the Warshel-type QM/MM methods and ONIOM methods. The link atom method has been criticised because it introduces extra unphysical atoms to the system, which come with associated extra degrees of freedom. Another problem is that a C-H bond is clearly not chemically exactly equivalent to a C-C bond. Despite these problems, the simplicity of the link atom method means that it is used widely in the QM/MM modelling of proteins and other biological molecules. ... 

Fig. 2.3 Concept of the two-layer ONIOM approach (ONIOM2) used for the QM/MM coupling in this work, connecting a high-level method - in our case DFTB - with a low-level method, in our case a force field approach.

Hybrid (usually referred to as QM/MM, but other combinations, such as QM/QM are possible) methods treat the most important part of a system with a higher level of theory than the remainder of the system (in the ONIOM method up to three layers are allowed) (56, 57, 58). Often the inq)ortant part is treated with some level of quantum mechanics and the remainder with molecular mechanics. Molecular mechanics treats a molecule in a ball-and-spring fashion (albeit a very sophisticated spring) in classical fields, but does not explicitly treat electrons in the Hamiltonian, and hence is incapable of treating problems where electronic phenomena are key. Disadvantages of these methods include the proper treatment of the interface between the QM and MM portions, the quantum portion still scales as the parent technique, and an unsatisfactory treatment of electron transport and optical properties. Along these lines, Sauer has introduced a combined quantum mechanics-interatomic potential function approach QM-Pot (59). 

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