Microscopic calculations of isospin-breaking corrections to superallowed beta decay.

The superallowed ß-decay rates that provide stringent constraints on physics beyond the standard model of particle physics are affected by nuclear structure effects through isospin-breaking corrections. The self-consistent isospin- and angular-momentum-projected nuclear density functional theory is used for the first time to compute those corrections for a number of Fermi transitions in nuclei from A=10 to A=74. The resulting leading element of the Cabibbo-Kobayashi-Maskawa matrix, |V(ud)|=0.97447(23), agrees well with the recent result of Towner and Hardy [Phys. Rev. C 77, 025501 (2008)].

Isospin mixing in nuclei within the nuclear density functional theory.

We present the self-consistent, nonperturbative analysis of isospin mixing using the nuclear density functional approach and the rediagonalization of the Coulomb interaction in the good-isospin basis. The unphysical isospin violation on the mean-field level, caused by the neutron excess, is eliminated by the proposed method. We find a significant dependence of the magnitude of isospin breaking on the parametrization of the nuclear interaction. A rough correlation has been found between the isospin-mixing parameter and the difference of proton and neutron rms radii.

N-Arylation of Sulfonamides on Solid Supports.

A general and mild method for the N-arylation of sulfonamides on solid supports is reported. Copper acetate, triethylamine mediated coupling of arylboronic acids at room temperature to solid-supported sulfonamides gave good to excellent yields of the desired N-arylsulfonamides. Sulfonamide bond cleavage of the o,p-dinitrobenzene(N-aryl)sulfonamide provides a route to N-arylated secondary amine products.

Rapid synthesis of RGD mimetics with isoxazoline scaffolds on solid phase: identification of alphavbeta3 antagonists lead compounds.

Isoxazoline containing RGD mimetics were rapidly synthesized on a solid phase to optimize linkers, regioisomers of isoxazoline scaffolds, and exosite binding groups to yield lead alphavbeta3 antagonists.

Design, synthesis, and in vitro activities of benzamide-core glycoprotein IIb/IIIa antagonists: 2,3-diaminopropionic acid derivatives as surrogates of aspartic acid.

In an effort to discover novel nonpeptide glycoprotein IIb/IIIa (GPIIb/IIIa, alpha IIb/beta 3) inhibitors, we investigated RGD mimetics featuring a 3-substituted benzoic acid as the core, benzamidine as the basic moiety, and a series of beta- and alpha-substituted beta-alanine derivatives as aspartic acid surrogates. It was found that the use of beta-methyl beta-alanine slightly improved the anti-aggregant potency in human platelet-rich plasma over the unsubstituted beta-alanine compound, while beta-substitution with a trifluoromethyl group resulted in considerable loss in activity. Significant enhancement (up to 100-fold) in potency was obtained when the beta-alanine was replaced with N2-substituted 1-2,3-diaminopropionic acid derivatives. Among the three types of alpha-substituents (carbamate, amide, and sulfonamide) investigated, no apparent preference was observed with respect to in vitro potency. However, alkyl groups were more favorable than arylalkyl groups (Cbz) in the carbamate analogues. We also investigated piperidine, piperazine, and N-formamidinopiperidine as replacements for the benzamidine moiety. The former two replacements led to a drop in potency while the latter replacement resulted in maintenance of activity as compared with the corresponding benzamidine analogue.

Membrane fusion activity of the influenza virus hemagglutinin: interaction of HA2 N-terminal peptides with phospholipid vesicles.

We have investigated the interaction of a number of synthetic 20-residue peptides, corresponding to the HA2 N-terminus of the influenza virus hemagglutinin (X31 strain), with phospholipid vesicles and monolayers. Besides the wild-type sequence, two peptides were studied with mutations corresponding to those previously studied in entire HA's expressed in transfected cells [Gething et al., (1986) J. Cell. Biol. 102, 11-23]. These mutations comprised a single Glu replacement for Gly at the N-terminus ("El" mutant) or at position 4 ("E4") of the HA2 subunit and were shown to produce striking alterations in virus-induced hemolysis and syncytia formation, especially for E1. The X31 "wild-type" (wt) peptide and its E4 variant are shown here to have the capacity to insert into phosphatidylcholine (POPC) large unilamellar vesicle (LUV) membranes in a strictly pH-dependent manner, penetration being marginal at pH 7.4 and significant at pH 5.0. Bilayer insertion was evident from a shift in the intrinsic Trp fluorescence of the wt and E4 peptides and from the induction of calcein leakage from POPC LUV and correlated well with the peptides' ability at pH 5.0 to penetrate into POPC monolayers at initial surface pressures higher than 30 mN/m. By contrast, the E1 peptide was found, at pH 5.0, to bind less tightly to vesicles (assessed by a physical separation method) and to cause much less leakage of POPC LUV than the wt, even under conditions where the peptides were bound to approximately the same extent. Consistent with the correlation between leakage and penetration observed for the wt peptide at pH 5 versus 7, the E1 peptide, even at low pH, showed much less lipid-vesicle-induced shift of its Trp fluorescence than wt, caused a much slower rate of leakage of vesicle contents, and did not insert into POPC monolayers at surface pressures beyond 28.5 mN/m. Circular dichroism spectroscopy measurements of peptides in POPC SUV showed that the conformations of all three peptides are sensitive to pH, but only the wt and E4 peptides became predominantly alpha-helical at acid pH.

Fluorescence analysis of tryptophan-containing variants of the LamB signal sequence upon insertion into a lipid bilayer.

To investigate the interaction of the LamB signal sequence with lipid bilayers, we have synthesized three tryptophan-containing analogues of the wild-type signal peptide. The tryptophan residues were used as intrinsic fluorescent probes of the N-terminal (position 5), central (position 18), and C-terminal (position 24) regions of the 25-residue peptide. The tryptophan substitutions did not significantly alter the physical properties of the wild-type signal peptide. In the presence of lipid vesicles which mimic the composition of the Escherichia coli inner membrane, the peptides adopt alpha-helical structure, and the tryptophan fluorescence emission maximum is shifted to shorter wavelength, indicating that the peptides insert into the acyl chain region of the lipid bilayer. Fluorescence quenching by soluble, aqueous-phase (I-), and membrane-resident (nitroxide-labeled lipids) quenchers was used to locate the tryptophans in each peptide within the bilayer. The C-terminus was interfacial while the central region of the signal sequence was deeply buried within the acyl chain region of the bilayer. The tryptophan at position 5 was buried but less deeply than the tryptophan at position 18. This topology is consistent with either a looped or a transmembrane orientation of signal peptide. However, either structure must accommodate the high helical content of the peptides in vesicles. These results indicate that the LamB signal sequence spontaneously inserts into the acyl chain region of lipid membranes in the absence of any of the proteins involved in protein secretion.

Phospholipid interactions of synthetic peptides representing the N-terminus of HIV gp41.

Peptides representing the N-terminal 23 residues of the surface protein gp41 of LAV1a and LAVmal strains of the human immunodeficiency virus were synthesized and their interactions with phospholipid vesicles studied. The peptides are surface-active and penetrate lipid monolayers composed of negatively charged but not neutral lipids. Similarly, the peptides induce lipid mixing and solute (6-carboxyfluorescein) leakage of negatively charged, but not neutral, vesicles. Circular dichroism and infrared spectroscopy show that at low peptide:lipid ratios (approximately 1:200), the peptides bind to negatively charged vesicles as alpha-helices. At higher peptide:lipid ratios (1:30), a beta conformation is observed for the LAV1a peptide, accompanied by a large increase in light scattering. The LAVmal peptide showed less beta-structure and induced less light scattering. With neutral vesicles, only the beta conformation and a peptide:lipid ratio-dependent increase in vesicle suspension light scattering were observed for both peptides. We hypothesize that the inserted alpha-helical form causes vesicle membrane disruption whereas the surface-bound beta form induces aggregation.