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A series of Polyhedral Oligomeric Silsesquioxane (POSS) propylmethacrylate (PMA) and styryl oligomers were prepared from POSS monomers, R7R'Si8O12, containing 1 functional R' group for polymerization and 7 inert R-groups where R = isobutyl (i-butyl), phenyl (Ph), cyclohexyl (Cy) or cyclopentyl (Cp). Both standard atom transfer radical polymerization (ATRP) and free radical syntheses, the latter employing azoisobutylnitrile as the free radical initiator were used in the syntheses. Matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectra were obtained in a new matrix, 4,4'-dihydroxyoctafluoroazobenzene which was especially designed for insoluble and intractable polymeric materials. Well-resolved series of oligomers were observed out to n = ~13 in both the linear and reflectron modes. Major peaks were assigned based on tandem mass spectrometry (MSMS) fragmentation patterns to give a consistent explanation of the observed spectra. In all cases, ionization of the ATRP products gave cationized parent ions in which the terminal Br atom was replaced by hydrogen. Additional observed peaks were due to loss of POSS side chains from the oligomer backbone. The free radical products were terminated with either one or two isobutylnitrile groups. Electrospray ionization (ESI) spectra were more complex than the MALDI-TOF but showed either identical parent ions or closely related hydroxylated parent ions., Pub. in the International Journal of Mass Spectrometry, p1-34, 2010.

The structure of the 21-30 fragment of the amyloid beta-protein (Abeta) was investigated by ion mobility mass spectrometry and replica exchange dynamics simulations. Mutations associated with familial Alzheimer's disease (E22G, E22Q, E22K, and D23N) of Abeta(21-30) were also studied, in order to understand any structural changes that might occur with these substitutions. The structure of the WT peptide shows a bend and a perpendicular turn in the backbone which is maintained by a network of D23 hydrogen bonding. Results for the mutants show that substitutions at E22 do little to alter the overall structure of the fragment. A substitution at D23 resulted in a change of structure for Abeta(21-30). A comparison of these gas-phase studies to previous solution-phase studies reveals that the peptide can fold in the absence of solvent to a structure also seen in solution, highlighting the important role of the D23 hydrogen bonding network in stabilizing the fragment's folded structure.

Abeta40 and Abeta42 are peptides that adopt similar random-coil structures in solution. Abeta42, however, is significantly more neurotoxic than Abeta40 and forms amyloid fibrils much more rapidly than Abeta40. Here, mass spectrometry and ion mobility spectrometry are used to investigate a mixture of Abeta40 and Abeta42. The mass spectrum for the mixed solution shows the presence of a heterooligomer composed of equal parts of Abeta40 and Abeta42. Ion mobility results indicate that this mixed species comprises an oligomer distribution extending to tetramers. Abeta40 alone produces such a distribution, whereas Abeta42 alone produces oligomers as large as dodecamers. This indicates that Abeta40 inhibits Abeta42 oligomerization.

Ion mobility and molecular modeling methods were used to investigate the gas phase conformational properties of Polyhedral Oligomeric Silsesquioxane (POSS) fluoride salts, where the fluoride is encapsulated within the POSS cage. Theoretical calculations demonstrate that the binding energy of fluoride to the interior of the POSS cage ranges from 70 to 270 kcal/mol as a function of substituent. Sodiated positive ions of the form HF@R8T8Na+ (T = SiO3/2, R = styrenyl, phenyl, and vinyl) were examined by MALDI; ESI was used to study the negative ions F-@R8T8 (R = styrenyl, phenyl, vinyl, trifluoropropyl, and nonafluorohexyl). The ion mobilities of these species were measured and used to calculate collision cross sections. These cross sections were compared to X-ray crystal structures and theoretical cross sections obtained from molecular mechanics and dynamics calculations. Experimental cross sections were consistent with all of the known X-ray crystal structures (styrenyl, vinyl and phenyl POSS species). The experimental cross sections also agreed with the calculated cross sections for each monomer species. Due to the compact nature of the POSS monomer cages, each sample had only one stable conformation, and only one low-energy family of structures was found for each set of sample calculations., Prepared in collaboration with the Department of Chemistry & Biochemistry, University of California, Santa Barbara, CA; the Department of Chemistry, Westmont College, Santa Barbara, CA; and ERC Inc., Edwards AFB, CA. Submitted for publication in the ACS Journal, Chemistry of Materials. The original document contains color images.

The effect of single amino acid substitutions associated with the Italian (E22K), Arctic (E22G), Dutch (E22Q) and Iowa (D23N) familial forms of Alzheimer's disease and cerebral amyloid angiopathy on the structure of the 21-30 fragment of the Alzheimer amyloid beta-protein (Abeta) is investigated by replica-exchange molecular dynamics simulations. The 21-30 segment has been shown in our earlier work to adopt a bend structure in solution that may serve as the folding nucleation site for Abeta. Our simulations reveal that the 24-28 bend motif is retained in all E22 mutants, suggesting that mutations involving residue E22 may not affect the structure of the folding nucleation site of Abeta. Enhanced aggregation in Abeta with familial Alzheimer's disease substitutions may result from the depletion of the E22-K28 salt bridge, which destabilizes the bend structure. Alternately, the E22 mutations may affect longer-range interactions outside the 21-30 segment that can impact the aggregation of Abeta. Substituting at residue D23, on the other hand, leads to the formation of a turn rather than a bend motif, implying that in contrast to E22 mutants, the D23N mutant may affect monomer Abeta folding and subsequent aggregation. Our simulations suggest that the mechanisms by which E22 and D23 mutations affect the folding and aggregation of Abeta are fundamentally different.