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A computational investigation of the electronic properties of an experimentally prepared ADADA helix indicates that the helix is held together with four strong hydrogen bonds as well as many other weak interactions. Determination of the electronic energy changes, as well as thermodynamic parameters, suggests that helix formation is a favorable process, driven by the formation of the hydrogen bonds. For instance, the unsubstituted helix has an electronic binding energy of -85.8 kJ/mol. Furthermore, the strength of binding can be tuned to some extent by the careful selection of substituents...

In order to elucidate the mechanisms of radical-initiated unfolding of a helix, the thermodynamic functions of hydrogen abstraction from the C(α), C(β), and amide nitrogen of Ala(3) in a homopeptapeptide (N-Ac-AAAAA-NH(2); A5) by HO(•), HO(2)(•), and O(2)(-•) were computed using the B3LYP density functional. The thermodynamic functions, standard enthalpy (ΔH(o)), Gibbs free energy (ΔG(o)), and entropy (ΔS(o)), of the reactants and products of these reactions were computed with A5 in the 3(10)-helical (A5(Hel)) and fully extended (A5(Ext)) conformations at the B3LYP/6-31G(d) and B3LYP/6-311+G(d,p) levels of theory, both in the gas phase and using the C-PCM implicit water model...

Four novel double-stranded RNA segments were detected in a Verticillium dahliae Kleb. strain (V. dahliae isolate 0-21), a causal fungal agent of Verticillium wilt disease of cotton. Each dsRNA genome segment contains a single large open reading frame (ORF) that encodes a distinctive protein with modest levels of sequence similarities to the corresponding putative proteins in the genus Chrysovirus. These include an RNA-dependent RNA polymerase (RdRp), a coat protein, an undefined replication-related protein and an ovarian tumor domain peptidase...

We measured the UV resonance Raman excitation profiles and Raman depolarization ratios of the arginine (Arg) vibrations of the amino acid monomer as well as Arg in the 21-residue predominantly alanine peptide AAAAA(AAARA)(3)A (AP) between 194 and 218 nm. Excitation within the π → π* peptide bond electronic transitions result in UVRR spectra dominated by amide peptide bond vibrations. The Raman cross sections and excitation profiles indicate that the Arg side chain electronic transitions mix with the AP peptide bond electronic transitions...

Heterocyclic diamidines are compounds with antiparasitic properties that target the minor groove of kinetoplast DNA. The mechanism of action of these compounds is unknown, but topological changes to DNA structures are likely to be involved. In this study, we have developed a polyacrylamide gel electrophoresis-based screening method to determine topological effects of heterocyclic diamidines on four minor groove target sequences: AAAAA, TTTAA, AAATT and ATATA. The AAAAA and AAATT sequences have the largest intrinsic bend, whereas the TTTAA and ATATA sequences are relatively straight...

a(n) ions are frequently formed in collision-induced dissociation (CID) of protonated peptides in tandem mass spectrometry (MS/MS) based sequencing experiments. These ions have generally been assumed to exist as immonium derivatives (-HN(+)═CHR). Using a quadrupole ion trap mass spectrometer, MS/MS experiments have been performed and the structure of a(n) ions formed from oligoglycines was probed by infrared spectroscopy. The structure and isomerization reactions of the same ions were studied using density functional theory...

Vrp1p (yeast WIP) forms a protein complex with Las17p (yeast WASP), however the physiological significance of the interaction has not been fully characterized. Vrp1p residues, (788)MPKPR(792) are essential for Vrp1p-Las17p interaction. While C-Vrp1p(364-817) complements all the defects of the vrp1Δ strain, C-Vrp1p(364-817)(5A) ((788)AAAAA(792)) does not complement any of the defects, due to its inability to localize to cortical patches. Targeting C-Vrp1p(364-817)(5A) to membranes using CAAX motif (C-Vrp1p(364-817)(5A)-CAAX) rescued the growth and endocytosis defect but not the actin patch polarization defect of vrp1Δ...

We used CD and UV resonance Raman spectroscopy to study the impact of alcohols on the conformational equilibria and relative Gibbs free energy landscapes along the Ramachandran Psi-coordinate of a mainly poly-Ala peptide, AP with an AAAAA(AAARA)(3)A sequence. 2,2,2-Trifluoroethanol (TFE) most stabilizes the alpha-helix-like conformations, followed by ethanol, methanol, and pure water. The pi-bulge conformation is stabilized more than the alpha-helix, while the 3(10)-helix is destabilized due to the alcohol-increased hydrophobicity...

We used CD, UV resonance Raman spectroscopy, and molecular dynamics simulation to examine the impact of salts on the conformational equilibria and the Ramachandran Psi angle (un)folding Gibbs free energy landscape coordinate of a mainly polyalanine alpha-helical peptide, AP of sequence AAAAA(AAARA)(3)A. NaClO(4) stabilizes alpha-helical-like conformations more than does NaCl, which stabilizes more than Na(2)SO(4) at identical ionic strengths. This alpha-helix stabilization ordering is the reverse of the Hofmeister series of anions in their ability to disorder water hydrogen bonding...

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UV resonance Raman (UVRR) excitation profiles and Raman depolarization ratios were measured for a 21-residue predominantly alanine peptide, AAAAA(AAARA) 3A (AP), excited between 194 and 218 nm. Excitation within the pi-->pi* electronic transitions of the amide group results in UVRR spectra dominated by amide vibrations. The Raman cross sections and excitation profiles provide information about the nature of the electronic transitions of the alpha-helix and polyproline II (PPII)-like peptide conformations...

Epithelial sodium channels (ENaCs) are assembled in the endoplasmic reticulum (ER) from alpha, beta, and gamma subunits, each with two transmembrane domains, a large extracellular loop, and cytoplasmic amino and carboxyl termini. ENaC maturation involves transit through the Golgi complex where Asn-linked glycans are processed to complex type and the channel is activated by furin-dependent cleavage of the alpha and gamma subunits. To identify signals in ENaC for ER retention/retrieval or ER exit/release, chimera were prepared with the interleukin alpha subunit (Tac) and each of the three cytoplasmic carboxyl termini of mouse ENaC (Tac-Ct) or with gamma-glutamyltranspeptidase and each of the three cytoplasmic amino termini (Nt-GGT)...

Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second-generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-duocarmycin SA...

The design, synthesis and DNA binding properties of a novel achiral and amino-containing seco-cyclopropylindoline analog (seco-amino-CI-TMI, 1) of the duocarmycins are described. Thermal induced DNA cleavage studies on pUC18 DNA revealed compound 1 to preferentially bind in the minor groove and to covalently react with AT-rich sequences, particularly at the underlined adenine-N3 group of 5'-AAAAA(865)-3'. This sequence specificity is similar to adozelesin and CC-1065. Using a 4-day continuous exposure, compound 1 inhibited the growth of K562 human chronic myeloid leukemia cells in culture...

One achiral seco-hydroxycyclopropylbenz[e]indolone (seco-CBI) (12) and seven achiral seco-amino-CBI (11a-g) analogues of CC-1065 and the duocarmycins were designed, synthesized and evaluated for their DNA-binding and anticancer properties. These compounds contain a core 2-chloroethylnaphthalene structure and they do not have a stereocenter. From thermal cleavage gel analyses, compounds 11a-g and 12 demonstrated similar covalent sequence specificity to adozelesin 3 and the racemic seco-CBI-TMI 4 for binding to the 5'-AAAAA(865)-3' site...

Eukaryotic chaperonins, the Cct complexes, are assembled into two rings, each of which is composed of a stoichiometric array of eight different subunits, which are denoted Cct1p-Cct8p. Overexpression of a single CCT gene in Saccharomyces cerevisiae causes an increase of the corresponding Cct subunit, but not of the Cct complex. Nevertheless, overexpression of certain Cct subunits, especially CCT6, suppresses a wide range of abnormal phenotypes, including those caused by the diverse types of conditional mutations tor2-21, lst8-2 and rsp5-9 and those caused by the concomitant overexpression of Sit4p and Sap155p...

Molecular dynamics simulations have been performed on netropsin in two different charge states and on distamycin binding to the minor groove of the DNA duplex d(CGCGAAAAACGCG).d(CGCGTTTTTCGCG). The relative free energy of binding of the two non-covalently interacting ligands was calculated using the thermodynamic integration method and reflects the experimental result. From 2 ns simulations of the ligands free in solution and when bound to DNA, the mobility and the hydrogen-bonding patterns of the ligands were studied, as well as their hydration...

Folding simulations of polyalanine peptides were carried out using an off-lattice Monte Carlo simulation technique. The peptide was represented as a chain of residues, each of which contains two interaction sites: one corresponding to the C(alpha) atom and the other to the side chain. A statistical potential was used to describe the interaction between these sites. The preferred conformations of the peptide chain on the energy surface, starting from several initial conditions, were searched by perturbations on its generalized coordinates with the Metropolis criterion...

A 28-residue beta-hairpin dimer (WKWK)2 with two Trp and two Lys residues on one face of each beta-sheet was shown to form a complex with single-stranded oligonucleotides at low micromolar concentrations. Each beta-hairpin of the dimer contains a cross-strand Trp-Trp pair in a diagonal orientation which has previously been shown to create a cleft for the intercalation of aromatic guests such as adenine (J. Am. Chem. Soc. 2003, 125, 9580). The beta-hairpin dimer binds 5-residue ssDNA sequences 5'-AAAAA-3', 5'-TTTTT-3', and 5'-CCCCC-3' in water with dissociation constants in the range of 12-30 muM...

The synthesis, DNA binding properties, and in vitro and in vivo anticancer activity of fifteen achiral seco-cyclopropylindoline (or achiral seco-CI) analogs (5a-o) of CC-1065 and the duocarmycins are described. The achiral seco-CI analogs contain a 4-hydroxyphenethyl halide moiety that is attached to a wide range of indole, benzimidazole, pyrrole, and pyridyl-containing noncovalent binding components. The 4-hydroxyphenethyl halide moiety represents the simplest mimic of the seco-cyclopropylpyrroloindoline (seco-CPI) pharmacophore found in the natural products, and it lacks a chiral center...