Molecular dynamics simulations of the orientation of Ni(II)•Gly-Gly-His and Ni(II)•Arg-Gly-His metallopeptide-DNA association

Ni(II)center dot Xaa-Gly-His metallopeptides (where Xaa is any R-amino acid) bind selectively to the minor groove of A/T-rich DNA regions as a function of their amino acid composition and chirality. Molecular dynamics simulations were performed to clarify the most likely binding orientations of Ni(II)center dot Gly-Gly-His and Ni( II)center dot L-Arg-Gly-His upon association with the B-form oligonucleotide d(CGCGAATTCGCG)(2). Upon examination of four possible docking orientations (I-IV), these studies indicated that both metallopeptides favor association with DNA via I, involving insertion of the edge of the metallopeptide containing the amino-terminal N-H and the imidazole pyrrole N-H group of His into the minor groove. These metallopeptide moieties play important roles in this DNA recognition mode by functioning as H-bond donors to minor groove acceptors such as the N3 of adenine or the O2 of thymine located on the floor of the minor groove. The positively charged side chain of L-Arg was found to enhance DNA recognition relative to that exhibited by Ni(II)center dot Gly-Gly-His through an increased electrostatic interaction, its favorable stereochemistry, and by providing a third point of contact with the minor groove floor. The simulation of orientation I was found to reproduce the experimentally supported DNA-metallopeptide orientation, revealing factors that are important for the further development of DNA-binding ligands.