Molecular mechanics for zinc complexes with fluctuating atomic charges

A recently developed force field with fluctuating atomic charges has been p arametrized to implement calculations for zinc complexes. The atomic charge s are calculated by means of a semi-empirical quantum chemical method (bond polarization theory, BPT). The major goal of this new force field is relia ble description of the geometry of zinc complexes and their intermolecular interactions with other molecular systems. It is possible to include all mu tual polarizations into the term for the electrostatic interaction using th e atomic charges obtained from the BPT. The treatment of the polarization e ffects including the whole system is one of the most important advantages o f this method in respect of alternative combinations of quantum chemical pr ocedures with force fields. If a ranking of complex stabilities is establis hed, polarization effects might significantly change the sequence. To reduce the number of force-field parameters, a new method was introduced for estimation of the equilibrium length of metal bonds to ligands. The me thod was tested to describe the structure of a variety of zinc complexes wh ere the structures are known from X-ray investigations. For small molecules , ab initio data were used as references. For the larger complexes, data fr om semi-empirical calculations were compared with the force field results. Significant deviations are observed for low coordination numbers and for so me five-coordinated compounds. The best geometries are obtained for [ZnL4]( 2+) complexes. For molecular dynamics simulations and conformational searches it is of int erest whether the non-bonded approach for the metal ligand system gives sta ble structures. Therefore, interaction energies of zinc ions with different numbers of water molecules were calculated and compared with results from ab initio calculations. Starting from [Zn(H2O)(3)](2+) the results strongly correlate linearly with the ab initio values and relative differences are reproduced satisfactorily. To test COSMOS on other types of ligand and more complicated systems we dec ided to apply a method to a number of complexes of pentahydrated Zn2+ with guanine, adenine, and the guanine-cytosine and adenine-thymine base pairs. Structures corresponding to energy minima are sought by molecular dynamics simulations and subsequent geometry optimization of coordinate snapshots. T he interaction energies of these structures are compared with results from ab initio calculations of similar structures. The absolute values obtained with COSMOS are usually too low but the relative stabilities are reproduced in agreement with the ab initio calculations. Finally the stability of a number of four-coordinated zinc complexes with n itrogen coordination was investigated. We used the energy values to predict the stability of zinc complexes of pseudo-peptide ligands before their syn thesis was performed.