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  1. Self-assembled Fe4 L 6 cage complexes with variable internal functions can be synthesized from a 2,7-dibromocarbazole ligand scaffold, which orients six functional groups to the cage interior. Both ethylthiomethylether and ethyldimethylamino groups can be incorporated. The cages show strong ligand-centered fluorescence emission and a broad range of guest binding properties. Coencapsulation of neutral organic guests is favored in the larger, unfunctionalized cage cavity, whereas the thioether cage has a more sterically hindered cavity that favors 1 : 1 guest binding. Binding affinities up to 10 6 M −1 in CH3 CN are seen. The dimethylamino cage is more complex, as the internal amines display partial protonation and can be deprotonated by amine bases. This amine cage displays affinity for a broad range of neutral organic substrates, with affinities and stoichiometries comparable to that of the similarly sized thioether cage. These species show that simple variations in ligand backbone allow variations in the number and type of functions that can be displayed towards the cavity of self-assembled hosts, which will have applications in biomimetic sensing, catalysis and molecular recognition.
    Free, publicly-accessible full text available July 1, 2023
  2. The ability to understand the function of a protein often relies on knowledge about its detailed structure. Sometimes, seemingly insignificant changes in the primary structure of a protein, like an amino acid substitution, can completely disrupt a protein's function. Long-lived proteins (LLPs), which can be found in critical areas of the human body, like the brain and eye, are especially susceptible to primary sequence alterations in the form of isomerization and epimerization. Because long-lived proteins do not have the corrective regeneration capabilities of most other proteins, points of isomerism and epimerization that accumulate within the proteins can severely hamper their functions and can lead to serious diseases like Alzheimer's disease, cancer and cataracts. Whereas tandem mass spectrometry (MS/MS) in the form of collision-induced dissociation (CID) generally excels at peptide characterization, MS/MS often struggles to pinpoint modifications within LLPs, especially when the differences are only isomeric or epimeric in nature. One of the most prevalent and difficult-to-identify modifications is that of aspartic acid between its four isomeric forms: l -Asp, l -isoAsp, d -Asp, and d -isoAsp. In this study, peptides containing isomers of Asp were analyzed by charge transfer dissociation (CTD) mass spectrometry to identify spectral features that could discriminatemore »between the different isomers. For the four isomers of Asp in three model peptides, CTD produced diagnostic ions of the form c n +57 on the N-terminal side of iso-Asp residues, but not on the N-terminal side of Asp residues. Using CTD, the l - and d forms of Asp and isoAsp could also be differentiated based on the relative abundance of y - and z ions on the C-terminal side of Asp residues. Differentiation was accomplished through a chiral discrimination factor, R , which compares an ion ratio in a spectrum of one epimer or isomer to the same ion ratio in the spectrum of a different epimer or isomer. The R values obtained using CTD are as robust and statistically significant as other fragmentation techniques, like radical directed dissociation (RDD). In summary, the extent of backbone and side-chain fragments produced by CTD enabled the differentiation of isomers and epimers of Asp in a variety of peptides.« less
    Free, publicly-accessible full text available March 14, 2023
  3. Solvochromatic effects are most frequently associated with solution-phase phenomena. However, in the gas phase, the absence of solvent leads to intramolecular solvation that can be driven by strong forces including hydrogen bonds and ion–dipole interactions. Here we examine whether isomerization of a single residue in a peptide results in structural changes sufficient to shift the absorption of light by an appended chromophore. By carrying out the experiments inside a mass spectrometer, we can easily monitor photodissociation yield as a readout for chromophore excitation. A series of peptides of different lengths, charge states, and position and identity of the isomerized residue were examined by excitation with both 266 and 213 nm light. The results reveal that differences in intramolecular solvation do lead to solvochromatic shifts in many cases. In addition, the primary product following photoexcitation is a radical. Ion–molecule reactions with this radical and adventitious oxygen were monitored and also found to vary as a function of isomeric state. In this case, differences in intramolecular solvation alter the availability of the reactive radical. Overall, the results reveal that small changes in a single amino acid can influence the overall structural ensemble sufficient to alter the efficiency of multiple gas-phase reactions.
  4. Recent studies have illuminated connections between spontaneous chemical reactions that cause isomerization at specific protein residues and various age-related diseases including cataracts and Alzheimer's. These discoveries provide impetus for better analytical methods to detect and characterize isomerization in proteins, which will enable a more complete understanding of the underlying relationship between these modifications and biology. Herein we employ a two-dimensional approach for identification of peptides isomers that also includes pinpointing of the modified residue. Collision-induced dissociation is used to fragment ions in the first dimension, followed by separation of the fragments with travelling-wave ion mobility. By comparing data obtained from both isomers, differences in either fragment-ion intensities or arrival-time distributions can be used to identify isomeric forms and the specific site of modification within the peptides. Synthetic peptide standards with sequences derived from long-lived proteins in the eye lens and isomerization at serine, aspartic acid, and glutamic acid were examined. Although both dimensions are capable of isomer identification, ion mobility is much better at determining the site of modification. In general, separation of isomeric forms by ion mobility is possible but does not follow predictable trends dictated by sequence or fragment-ion length. In most cases, however, the site of isomerizationmore »can be precisely determined.« less