3-dimensionalSU(2) lattice gauge theory in terms of gauge invariant variables

As a first step towards a duality transformation for theSU(2) lattice gauge theory in 3 dimensions, the integration over all gauge variant variables is performed explicitly after introducing gauge invariant auxiliary variables. The resulting new Hamiltonian is complex and involves a sum over closed loops. Each of these loops is confined to an elementary cube of a dual lattice. Like in a previous investigation for theO(4) symmetric Heisenberg ferromagnet Rühl's boson representation is used to derive the result.     

A Diazirine-Modified Membrane Lipid to Study Peptide/Lipid Interactions – Chances and Challenges

Although incorporation of photo-activatable lipids into membranes potentially opens up novel avenues for investigating interactions with proteins, the question of whether diazirine-modified lipids are suitable for such studies, remains under debate. Focusing on the potential for studying lipid/peptide interactions by cross-linking mass spectrometry (XL-MS), we developed a diazirine-modified lipid (DiazPC), and examined its behaviour in membranes incorporating the model α-helical peptide LAVA20. We observed an unexpected backfolding of the diazirine-containing stearoyl chain of the lipid. This surprising behaviour challenges the potential application of DiazPC for future XL-MS studies of peptide and protein/lipid interactions. The observations made for DiazPC most likely represent a general phenomenon for any type of membrane lipids with a polar moiety incorporated into the alkyl chain. Our finding is therefore of importance for future protein/lipid interaction studies relying on modified lipid probes.     

Observable azacyclobutenone ylides with antiaromatic character from 2-diazoacetyl-azaaromatics

Azacyclobutenone ylides 2 and 11 were generated in solution by laser flash photolysis of 2-diazoacetylpyridine (1) and 3-diazoacetylpyridazine (10), respectively, together with the corresponding ketenes. The ylides were identified by their characteristic IR and UV spectra: 2, nu (CH3CN) 1725 cm(-1), lambdamax 360 and 550 (br) nm; 11, nu (CH3CN) 1776 cm(-1), lambdamax 370 and 550 (br) nm. 2-Triisopropylsilyldiazoacetylpyridine 20 upon photolysis at 5 degrees C in CH3CN forms the ylide 21 as a rather persistent (T1/2 2 h at 25 degrees C) purple solution, nu (CH3CN) 1718 cm(-1), lambdamax 245, 378 and 546 (br) nm, but no ketene is observed. Quinolyl ylide 14 and pyridyl ylides 17 and 19 with Me and 2-pyridyl substituents, respectively, with characteristic IR and UV spectra were also generated. The 1H NMR spectrum of the pyridyl ring of 21 shows substantial upfield shifts relative to those of 20. Calculated nucleus-independent chemical shifts (NICS) for 2, 11, and 21 are comparable to those for benzocyclobutadiene (22) and benzocyclobutenone enolate (23), with substantial positive values for the 4-membered rings, while the NICS values for the 6-membered rings are significantly more positive than for benzene or pyridine. Significant bond alternation is also found in the calculated ylide structures, and these results suggest strong antiaromatic character for the 4-membered rings of 2, 11, 14, 17, 19, and 21, and greatly reduced aromatic character for the 6-membered rings.     

Evidence for a reverse U-shaped conformation of single-chain bolaamphiphiles at the air-water interface

Infrared reflection absorption spectroscopy and X-ray reflectivity have been used to elucidate the molecular orientation and hydrocarbon chain conformation and packing of the symmetric long-chain bolaamphiphiles dotriacontane-1,1'-diyl-bis-[2-(trimethylammonio)ethylphosphate] (PC-C32-PC) and dotriacontane-1,1'-diyl-bis-[2-(dimethylammonio)ethylphosphate] (Me2PE-C32-Me2PE) at the air-water interface. At low surface pressures, these bipolar amphiphiles are found to lie flat on the water surface with a disordered chain. With increasing surface pressure, the alkyl chain becomes more ordered. Concomitantly, the chain is bent pointing into the air, whereas both polar headgroups keep contact with the water subphase. At an area of 0.9-1.1 nm2 per molecule, a surface pressure plateau is reached for both bolaamphiphiles, where the molecules adopt a reverse U-shaped conformation with a strongly tilted alkyl chain. Further compression leads to the formation of 3-D aggregates.     

Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins

Amyloidoses are diseases characterized by abnormal protein folding and self-assembly, for which no cure is available. Inhibition or modulation of abnormal protein self-assembly, therefore, is an attractive strategy for prevention and treatment of amyloidoses. We examined Lys-specific molecular tweezers and discovered a lead compound termed CLR01, which is capable of inhibiting the aggregation and toxicity of multiple amyloidogenic proteins by binding to Lys residues and disrupting hydrophobic and electrostatic interactions important for nucleation, oligomerization, and fibril elongation. Importantly, CLR01 shows no toxicity at concentrations substantially higher than those needed for inhibition. We used amyloid β-protein (Aβ) to further explore the binding site(s) of CLR01 and the impact of its binding on the assembly process. Mass spectrometry and solution-state NMR demonstrated binding of CLR01 to the Lys residues in Aβ at the earliest stages of assembly. The resulting complexes were indistinguishable in size and morphology from Aβ oligomers but were nontoxic and were not recognized by the oligomer-specific antibody A11. Thus, CLR01 binds already at the monomer stage and modulates the assembly reaction into formation of nontoxic structures. The data suggest that molecular tweezers are unique, process-specific inhibitors of aberrant protein aggregation and toxicity, which hold promise for developing disease-modifying therapy for amyloidoses.     

Challenges in optimizing a prostate carcinoma binding peptide, identified through the phage display technology

The transfer of peptides identified through the phage display technology to clinical applications is difficult. Major drawbacks are the metabolic degradation and label instability. The aim of our work is the optimization of DUP-1, a peptide which was identified by phage display to specifically target human prostate carcinoma. To investigate the influence of chelate conjugation, DOTA was coupled to DUP-1 and labeling was performed with 111In. To improve serum stability cyclization of DUP-1 and targeted D-amino acid substitution were carried out. Alanine scanning was performed for identification of the binding site and based on the results peptide fragments were chemically synthesized. The properties of modified ligands were investigated in in vitro binding and competition assays. In vivo biodistribution studies were carried out in mice, carrying human prostate tumors subcutaneously. DOTA conjugation resulted in different cellular binding kinetics, rapid in vivo renal clearance and increased tumor-to-organ ratios. Cyclization and D-amino acid substitution increased the metabolic stability but led to binding affinity decrease. Fragment investigation indicated that the sequence NRAQDY might be significant for target-binding. Our results demonstrate challenges in optimizing peptides, identified through phage display libraries, and show that careful investigation of modified derivatives is necessary in order to improve their characteristics.