Molecular modelling molecules proteins quantum mechanics

One tool for working toward this objective is molecular mechanics. In this approach, the bonds in a molecule are treated as classical objects, with continuous interaction potentials (sometimes called force fields) that can be developed empirically or calculated by quantum theory. This is a powerful method that allows the application of predictive theory to much larger systems if sufficiently accurate and robust force fields can be developed. Predicting the structures of proteins and polymers is an important objective, but at present this often requires prohibitively large calculations. Molecular mechanics with classical interaction potentials has been the principal tool in the development of molecular models of polymer dynamics. The ability to model isolated polymer molecules (in dilute solution) is well developed, but fundamental molecular mechanics models of dense systems of entangled polymers remains an important goal. 

Figure 1 In a QM/MM calculation, a small region is treated by a quantum mechanical (QM) electronic structure method, and the surroundings treated by simpler, empirical, molecular mechanics. In treating an enzyme-catalysed reaction, the QM region includes the reactive groups, with the bulk of the protein and solvent environment included by molecular mechanics. Here, the approximate transition state for the Claisen rearrangement of chorismate to prephenate (catalysed by the enzyme chorismate mutase) is shown. This was calculated at the RHF(6-31G(d)-CHARMM QM-MM level. The QM region here (the substrate only) is shown by thick tubes, with some important active site residues (treated by MM) also shown. The whole model was based on a 25 A sphere around the active site, and contained 4211 protein atoms, 24 atoms of the substrate and 947 water molecules (including 144 water molecules observed by X-ray crystallography), a total of 7076 atoms. The results showed specific transition state stabilization by the enzyme. Comparison with the same reaction in solution showed that transition state stabilization is important in catalysis by chorismate mutase78.

Alternatively, different molecular models may be used in different regions. The combination of quantum mechanics (QM) (close to the docking site) and molecular mechanics (MM) (in the rest of the protein) methods allows one to predict the behavior of molecules docking on proteins. Particular attention must also be paid to an accurate joining of the two regimes at the boundary region. 

Quantum mechanical study of the photoisomerization reaction of PYP began with calculations of the adiabatic potential energy surfaces of small model compounds of the chromophore (Yamada et al. 2001). However, to fully describe the protein-chromophore interaction, we had to include the entire protein molecule in the photoisomerization reaction. Recently, QM/MM (Hayashi and Ohmine 2000) and the ONIOM (Yamada et al. 2002 Vreven and Morokuma 2003), both of which are hybrid methods of high- and low-level calculations, have been used for large molecular systems. We performed the ONIOM (IMOMM) calculations on PYP to elucidate the role of the protein enviroiunent (Yamada etal. 2004a,b). We also investigated the origin of the force that drives photoisomerization. 

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