Molecular-dynamics simulation of the beta domain of metallothionein with a semi-empirical treatment of the metal core.

The three-metal-containing beta domain of rat liver metallothionein-2 in aqueous solution was simulated with different metal contents. The Cd(3), the CdZn(2), and the Zn(3) variant were investigated using a conventional molecular dynamics simulation, as well as a simulation with a semi-empirical quantum-chemical description (MNDO and MNDO/d) of the metal core embedded in a classical environment. For the purely classical simulations, the standard GROMOS96 force-field parameters were used, and parameters were estimated for cadmium. The results of both kinds of simulations were compared to each other and to the corresponding experimental X-ray crystallographic and NMR solution data. The purely classical simulations were found to produce a too compact metal cluster with partially incorrect geometries, which affected the enfolding protein backbone structure. The inclusion of MNDO/d for the treatment of the metal cluster improved the results to give correct cluster geometries and an overall protein structure in agreement with the experiment. The metal cluster and the cysteine residues bound to it are structurally stable, while the irregular polypeptide backbone loops between the cysteines exhibit a considerable flexibility. MNDO without extension to d orbitals failed to maintain the structure of the metal core.