Pseudobond

The calculation of the free energies of enzymes by this procedure provides several advantages. In this approach, the MEP is determined in the enzyme environment with a smooth connection between the QM and MM subsystems by means of the pseudobond QM/MM method [39], Also, the polarization effects of the enzyme environment on the QM subsystem have been included [13]. 

In all cases the calculations were performed using QM/MM methodology that includes the pseudobond model for the QM/MM boundary [13,39,41]. This methodology has been implemented in a modified version of Gaussian 98 [42], which interfaces to a modified version of TINKER [43], The AMBER94 all-atom force field parameter set [44] and the TIP3P [45] model for water were used. 

Keywords Ab initio QM/MM method, Pseudobond approach, Enzyme catalysis, Reaction... 

In our simulations of histone modifying enzymes, the computational approaches centered on the pseudobond ab initio quantum mechanical/molecular mechanical (QM/MM) approach. This approach consists of three major components [20,26-29] a pseudobond method for the treatment of the QM/MM boundary across covalent bonds, an efficient iterative optimization procedure which allows for the use of the ab initio QM/MM method to determine the reaction paths with a realistic enzyme environment, and a free energy perturbation method to take account... 

Figure 12-1. Illustration of the difference between the pseudobond approach and the conventional link atom approach in the treatment of the QM/MM boundary problem...

In order to improve the accuracy and applicability of the pseudobond approach, very recently we have developed a new formulation to construct this seven-valence-electron boundary atom [29], The key difference is that the seven-valence-electron boundary atom has its own basis set instead of that of fluorine. Here a STO-2G... 

Zhang Y (2006) Pseudobond ab initio QM/MM approach and its applications to enzyme reactions. Theor Chem Acc 116 43-50... 

Zhang Y, Lee TS, Yang W (1999) A pseudobond approach to combining quantum mechanical and molecular mechanical methods. J Chem Phys 110 46-54... 

Zhang Y (2005) Improved pseudobonds for combined ab initio quantum mechanical/molecular mechanical methods. J Chem Phys 122 024114... 

In the structurally coupled QM/MM implementation of Zhang et al. [55, 56], in which the QM/MM boundary was treated by use of the pseudobond approach [55, 57], the QM/MM minimization of the QM part is combined with FEP calculations. In this procedure the energy profile of the enzyme reaction is first determined by use of QM/MM energy minimizations. The structures and charges of the QM atoms are then used, in the same manner as in the QM/FE method, to determine the role of environment on the energy profile of the reaction. In this way the effects of a large number of MM conformations of protein and solvent environment can be included in the total energies. 

In the pseudobond method of Yang and coworkers [47] a pseudobond is formed with one free-valence atom with an effective core potential (optimized to reproduce the length and strength of the real bond). This core potential can be applied in Hartree-Fock and density functional calculations and is designed to be independent of the choice of the MM force field. 

Figure 3-4. Representation of the molecule in the ENM. Each node represents the center of the bead which is the C carbon (CA) in case of one-bead protein models. The lines (pseudobonds) represent the harmonic interactions between beads that are within certain distance apart...

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