Molecular mechanics reactions

Ridder, L., Mulholland, A.J., Rietjens, I.M.C.M., and Vervoort J., Combined quantum mechanical and molecular mechanical reaction pathway calculation for aromatic hydroxylation by p-hydroxybenzoate-3-hydroxylase, J. Mol. Graphics Modeling, 17, 163-175, 1999. 

A large number of experiments were performed at 633, 667, 710, 737, and 800 °K with initial H2/I2 ratios of 0.1-3. Data at a single temperature show that a molecular mechanism (reactions (1) and (2)) alone is not sufficient. The addition of reactions (3) through (6) to the mechanism does however provide a satisfactory explanation of the experimental observations. At 800 °C the radical mechanism predominates. 

Theoretical approaches to the study of protein structure and function draw upon concepts and techniques from theoretical chemistry, including molecular mechanics, reaction dynamics, quantum and statistical mechanics (Brooks et al. 1988). Molecular mechanics methods were first developed for the study of small organic molecules (Barton 1948 Westheimer 1956 Hendrickson 1961 Wiberg 1965 Allinger et al. 1967 ... 

EELS Electron energy loss spectroscopy The loss of energy of low-energy electrons due to excitation of lattice vibrations. Molecular vibrations, reaction mechanism... 

For this reason, there has been much work on empirical potentials suitable for use on a wide range of systems. These take a sensible functional form with parameters fitted to reproduce available data. Many different potentials, known as molecular mechanics (MM) potentials, have been developed for ground-state organic and biochemical systems [58-60], They have the advantages of simplicity, and are transferable between systems, but do suffer firom inaccuracies and rigidity—no reactions are possible. Schemes have been developed to correct for these deficiencies. The empirical valence bond (EVB) method of Warshel [61,62], and the molecular mechanics-valence bond (MMVB) of Bemardi et al. [63,64] try to extend MM to include excited-state effects and reactions. The MMVB Hamiltonian is parameterized against CASSCF calculations, and is thus particularly suited to photochemistry. 

Singh, U.C., Kollman, P.A. A combined ab initio quantum mechanical and molecular mechanical method for carrying out simulations on complex molecular systems Applications to the CH3CI 4- Cl exchange reaction and gas phase protonation of polyethers. J. Comput. Chem. 7 (1986) 718-730. 

For many applications, especially studies on enzyme reaction mechanisms, we do not need to treat the entire system quantum mechanically. It is often sufficient to treat the center of interest (e.g., the active site and the reacting molecules) quantum mechanically. The rest of the molecule can be treated using classical molecular mechanics (MM see Section 7.2). The quantum mechanical technique can be ab-initio, DFT or semi-empirical. Many such techniques have been proposed and have been reviewed and classified by Thiel and co-workers [50] Two effects of the MM environment must be incorporated into the quantum mechanical system. 

The classical introduction to molecular mechanics calculations. The authors describe common components of force fields, parameterization methods, and molecular mechanics computational methods. Discusses th e application of molecular mechanics to molecules comm on in organic,and biochemistry. Several chapters deal w ith thermodynamic and chemical reaction calculations. 

Dne approach to the simulation of chemical reactions in solution is to use a combination t)f [uantum mechanics and molecular mechanics. The reacting parts of the system are treated [uantum mechanically, with the remainder being modelled using the force field. The total mergy Etot for the system can be written ... 

W C, A Tempcz)rrk, R C Hawley and T Hendrickson 1990. Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics. Journal of the American Chemical Society 112 6127-6129. ensson M, S Humbel, R D J Froese, T Matsubara, S Sieber and K Morokuma 1996. ONIOM A Multilayered Integrated MO + MM Method for Geometry Optimisations and Single Point Energy Predictions. A Test for Diels-Alder Reactions and Pt(P(t-Bu)3)2 + H2 Oxidative Addition. Journal of Physical Chemistry 100 19357-19363. 

Molecular mechanics methods are not generally applicable to structures very far from equilibrium, such as transition structures. Calculations that use algebraic expressions to describe the reaction path and transition structure are usually semiclassical algorithms. These calculations use an energy expression fitted to an ah initio potential energy surface for that exact reaction, rather than using the same parameters for every molecule. Semiclassical calculations are discussed further in Chapter 19. 

The disadvantage of molecular mechanics is that there are many chemical properties that are not even defined within the method, such as electronic excited states. Since chemical bonding tenns are explicitly included in the force field, it is not possible without some sort of mathematical manipulation to examine reactions in which bonds are formed or broken. In order to work with extremely large and complicated systems, molecular mechanics software packages often have powerful and easy-to-use graphic interfaces. Because of this, mechanics is sometimes used because it is an easy, but not necessarily a good, way to describe a system. 

The technique most often used (i.e., for an atom transfer) is to hrst plot the energy curve due to stretching a bond that is to be broken (without the new bond present) and then plot the energy curve due to stretching a bond that is to be formed (without the old bond present). The transition structure is next dehned as the point at which these two curves cross. Since most molecular mechanics methods were not designed to describe bond breaking and other reaction mechanisms, these methods are most reliable when a class of reactions has been tested against experimental data to determine its applicability and perhaps a suitable correction factor. 

The level of theory necessary for computing PES s depends on how those results are to be used. Molecular mechanics calculations are often used for examining possible conformers of a molecule. Semiempiricial calculations can give a qualitative picture of a reaction surface. Ah initio methods must often be used for quantitatively correct reaction surfaces. Note that size consistent methods must be used for the most accurate results. The specific recommendations given in Chapter 18 are equally applicable to PES calculations. 

The Poisson equation has been used for both molecular mechanics and quantum mechanical descriptions of solvation. It can be solved directly using numerical differential equation methods, such as the finite element or finite difference methods, but these calculations can be CPU-intensive. A more efficient quantum mechanical formulation is referred to as a self-consistent reaction field calculation (SCRF) as described below. 

Molecular mechanics methods have been used particularly for simulating surface-liquid interactions. Molecular mechanics calculations are called effective potential function calculations in the solid-state literature. Monte Carlo methods are useful for determining what orientation the solvent will take near a surface. Molecular dynamics can be used to model surface reactions and adsorption if the force held is parameterized correctly. 

The mechanism of the synthesis reaction remains unclear. Both a molecular mechanism and an atomic mechanism have been proposed. Strong support has been gathered for the atomic mechanism through measurements of adsorbed nitrogen atom concentrations on the surface of model working catalysts where dissociative N2 chemisorption is the rate-determining step (17). The likely mechanism, where (ad) indicates surface-adsorbed species, is as follows ... 

A final important area is the calculation of free energies with quantum mechanical models [72] or hybrid quanmm mechanics/molecular mechanics models (QM/MM) [9]. Such models are being used to simulate enzymatic reactions and calculate activation free energies, providing unique insights into the catalytic efficiency of enzymes. They are reviewed elsewhere in this volume (see Chapter 11). 

An example of the application of molecular mechanics in the investigation of chemical reactions is a study of the correlation between steric strain in a molecule and the ease of rupture of carbon-carbon bonds. For a series of hexasubstituted ethanes, it was found that there is a good correlation between the strain calculated by the molecular mechanics method and the rate of thermolysis. Some of the data are shown in Table 3.3. 

---