DNA Cleaving "Tandem-Array" Metallopeptides Activated With KHSO: Towards the Development of Multi-Metallated Bioactive Conjugates and Compounds.

Amino terminal peptides of the general form Gly-Gly-His have been used to introduce single sites of metal binding and redox activity into a wide range of biomolecules to create bioactive compounds and conjugates capable of substrate oxidation. We report here that Gly-Gly-His-like peptides linked in a tandem fashion can also be generated leading to multi-metal binding arrays. While metal binding by the native Gly-Gly-His motif (typically to Cu, Ni, or Co) requires a terminal peptide amine ligand, previous work has demonstrated that an ornithine (Orn) residue can be substituted for the terminal Gly residue to allow solid-phase peptide synthesis to continue via the side chain -δ.

Genome-Targeted Drug Design: Understanding the Netropsin-DNA Interaction.

Knowledge of the sequence of the human genome has provided significant opportunities to exploit DNA as a target in the rational design of therapeutic agents. Among agents that target DNA, netropsin exhibits a strong preference for binding A/T rich regions. In order to investigate the key factors responsible for DNA recognition and binding by netropsin, molecular dynamics simulations were carried out on a DNA-netropsin complex in which two netropsin molecules are bound to each AATT site of the 16-mer d(CTTAATTCGAATTAAG)(2).

Enaminones 8: CoMFA and CoMSIA studies on some anticonvulsant enaminones.

3D-QSAR studies comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 26 structurally diverse subcutaneous pentylenetetrazol (scPTZ) active enaminone analogues, previously synthesized in our laboratory. CoMFA and CoMSIA were employed to generate models to define the specific structural and electrostatic features essential for enhanced binding to the putative GABA receptor. The 3D-QSAR models demonstrated a reliable ability to predict the CLogP of the active anticonvulsant enaminones, resulting in a q(2) of 0.

DNA-fiber EPR investigation of the influence of amino-terminal residue stereochemistry on the DNA binding orientation of Cu(II).Gly-Gly-His-derived metallopeptides.

DNA fiber EPR was used to investigate the DNA binding stabilities and orientations of Cu(II).Gly-Gly-His-derived metallopeptides containing D- vs. L-amino acid substitutions in the first peptide position.

Molecular Dynamics Simulations of the Orientation of Ni(II)•Gly-Gly-His and Ni(II)•Arg-Gly-His Metallopeptide-DNA Association.

Ni(II)•Xaa-Gly-His metallopeptides (where Xaa is any α-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)•Gly-Gly-His and Ni(II)•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.

Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms.

Alternative splicing of pre-mRNA generates two or more protein isoforms from a single gene, thereby contributing to protein diversity. Despite intensive efforts, an understanding of the protein structure-function implications of alternative splicing is still lacking. Intrinsic disorder, which is a lack of equilibrium 3D structure under physiological conditions, may provide this understanding.

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.

Ni(II).Arg-Gly-His-DNA interactions: investigation into the basis for minor-groove binding and recognition.

A study of the minor-groove recognition of A/T-rich DNA sites by Ni(II).L-Arg-Gly-His and Ni(II).D-Arg-Gly-His was carried out with a fluorescence-based binding assay, one- and two-dimensional (1D and 2D) NMR methodologies, and molecular simulations.