Pseudobond method

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... 

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. 

Boundary atom schemes have been developed to avoid the artifacts introduced by a link atom. The boundary atom appears as a normal MM atom in the MM calculation, while carrying QM features to saturate the QM-MM bond and to mimic the electronic properties of the MM side. The QM interactions are achieved by placing a pseudopotential at the position of the boundary atom, parameterized to reproduce electronic properties of certain chemical end group, e.g., a methyl group in the case of a cut C-C bond. Among the various flavors that have been proposed, the pseudobond method for first principles QM calculations (Zhang 2005, 2006 Zhang et al. 1999) and the pseudopotential approach for plane-wave DFT (Laio et al. 2002) are the most relevant in the present context. 

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]. 

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

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. 

---