Studies on the Structural Properties of NAMI-A in Aqueous Solution by Combined QM and ABEEM/MM Method

Since 1970s carried out by Warshel et al. QM/MM method has been successfully applied to a wide range of reactions in solution, enzyme and proteins. Up to now, QM has been combined with some popular force fields, like OPLS-AA, Amber or CHARMM. In this work, QM has been combined with ABEEM fluctuating charge force field (ABEEM/MM). ABEEM/MM is a polarizable force field in which the ABEEM sigma pi method has been fused. ABEEM sigma pi method, the atom-bond electronegativity equalization method, was proposed and developed by Yang et al. based on electronegativity equalization principle in density functional theory (DFT). In order to further improve the feasibility of combining QM with ABEEM/MM, the properties of anticancer drug imidazolium [ trans-tetrachloro(DMSO)(imidazole) ruthenate(III)](NAMI-A) in aqueous solution have been investigated, such as structures, polarization energies, charge distributions and radial distribution functions. All the configurations were optimized at B3LYP/6-31G(d,p)//LanL2DZ (for Ru) level by using the Gaussian 03 program. The isoelectric focusing polarized continuum model (IEF-PCM) with UAHF atomic radii was employed for PCM model, and the dielectric constant of water (epsilon=78.39) was used to approximate the effect of aqueous solution. In QM/MM method, QM and MM regions were optimized by using different methods. The convergence criteria that the maximum gradient of energy is less than 5x10(-4) a.u. in QM region and the RMS gradient is less than 1x10(-3) kcal.mol(-1).A(-1) in MM region was adopted for the iterative optimization. After MM minimization, MM region participated as point charges to impact the optimization of QM. No cutoff was introduced to QM and MM interactions. Iterative optimizations have accomplished until reaching the convergence criteria. All the MD simulations were performed by using the modified Tinker program in the NVT ensemble at 298 K with Berendsen thermostats, the velocity Verlet integrator, and a time step of 1 fs. To prepare a reasonable structure of solvent, the periodic boundary condition and the minimum image convention were used. The cutoff radius for nonbonded interactions was 9.0 angstrom. Dynamic simulations consisted of 150 ps of equilibration run and 50 ps of averaging run. Comparisons of structure for NAMI-A obtained by PCM model, QM/MM (OPLS-AA) and QM/MM (ABEEM/MM) methods have been carried out. Our results show that NAMI-A interact with aqueous solution by forming hydrogen bonds, and the solvent does have a great impact on both structure and atomic charge of NAMI-A by polarization effect. How to deal with the polarization plays a key role in accurately describing the properties of NAMI-A. Since ABEEM/MM can fast and accurately describe the electrostatic interaction between molecules, thus combining QM with ABEEM/MM has been further proved to be a development of QM/MM method.