Molecular dynamics simulation of metallothionein-drug complexes.

The intermolecular interactions of metallothionein with nitrogen mustard drugs were studied by molecular dynamics simulations. Previous laboratory experiments have defined selective alkylation of two cysteine residues, and selective binding was proposed to precede alkylation. The present study provides information about accessibility to cysteines based on evaluating the intermolecular energies and distances in the first few ps of dynamics simulations. A series of dynamics simulations was performed with three drug molecules positioned at the eight most solvent accessible cysteine residues of the dimeric form of the protein. Sites proximal to the sulfhydryl groups of Cys-33 and Cys-48 were found to be the most favorable for complexing the aziridinium forms of chlorambucil, melphalan, and mechlorethamine. The sites for preferential binding are in qualitative agreement with the sites of selective alkylation defined experimentally.