Diastereoselective DNA cleavage recognition by Ni(II) x Gly-Gly-His-derived metallopeptides.
Site-selective DNA cleavage by diastereoisomers of Ni(II) x Gly-Gly-His-derived metallopeptides was investigated through high-resolution gel analyses and molecular dynamics simulations. Ni(II) x L-Arg-Gly-His and Ni(II) x D-Arg-Gly-His (and their respective Lys analogues) targeted A/T-rich regions; however, the L-isomers consistently modified a subset of available nucleotides within a given minor groove site, while the D-isomers differed in both their sites of preference and their ability to target individual nucleotides within some sites. In comparison, Ni(II) x L-Pro-Gly-His and Ni(II) x D-Pro-Gly-His were unable to exhibit a similar diastereoselectivity. Simulations of the above systems, along with Ni(II) x Gly-Gly-His, indicated that the stereochemistry of the amino-terminal amino acid produces either an isohelical metallopeptide that associates stably at individual DNA sites (L-Arg or L-Lys) or, with D-Arg and D-Lys, a noncomplementary metallopeptide structure that cannot fully employ its side chain nor amino-terminal amine as positional stabilizing moieties. In contrast, amino-terminal Pro-containing metallopeptides of either stereochemistry, lacking an extended side chain directed toward the minor groove, did not exhibit a similar diastereoselectivity. While the identity and stereochemistry of amino acids located in the amino-terminal peptide position influenced DNA cleavage, metallopeptide diastereoisomers containing L- and D-Arg (or Lys) within the second peptide position did not exhibit diastereoselective DNA cleavage patterns; simulations indicated that a positively charged amino acid in this location alters the interaction of the metallopeptide equatorial plane and the minor groove leading to an interaction similar to Ni(II) x Gly-Gly-His.
Fang
Ya-Yin
YY
Department of Chemistry & Chemical Biology, Purdue School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202-3274, USA.
Claussen
Craig A
CA
Lipkowitz
Kenny B
KB
Long
Eric C
EC
D001345:Autoradiography; D001483:Base Sequence; D002413:Cations, Divalent; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D008667:Metalloproteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009532:Nickel / Q000737:chemistry* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity
D002413:Cations, Divalent; D008667:Metalloproteins; D009842:Oligopeptides; C037026:diglycyl-histidine; D009532:Nickel; D004247:DNA