In this award, funded by the Chemical Structure, Dynamics and Mechanisms Program of the Division of Chemistry, Professor Timothy Zwier of Purdue University and his graduate and undergraduate students are carrying out experimental studies of the conformational preferences and laser-induced isomerization of a series of model peptides, synthetic foldamers, and peptide aggregates, studied either as isolated molecules cooled in a supersonic expansion or as ions cooled to 10K in a cryo-cooled ion trap. Neutral peptides and foldamers are being studied using laser-induced fluorescence (LIF), mass-resolved resonant two-photon ionization (R2PI), IR-UV and UV-UV hole-burning methods to determine the number of conformational isomers present and obtain their single-conformation infrared and ultraviolet spectra. From these spectra, the researchers deduce the preferred intramolecular H-bonding arrangements, discover their unique spectral signatures, provide benchmark tests of the accuracy of calculations, and provide a test bed for emerging methods for quantifying non-bonding interactions in large molecules. Proline-rich alpha-peptides that form loose helices in solution are being studied in isolated form to determine their inherent conformational preferences in the absence of solvent. Synthetic foldamers composed of several types of constrained peptides, prepared collaboratively by the Gellman group, are being studied to test how elongation of the peptide backbone in combination with constraints from cyclic residues, affects the conformational preferences. In expanding these studies to include ions, Professor Zwier and his team are using a newly constructed multi-stage mass spectrometer that incorporates a cryocooled ion trap capable of carrying out single-conformation spectroscopy on larger peptides and peptide aggregates, using photofragment spectroscopy. Here the focus is on longer peptide sequences known in solution to form prototypical secondary structures. Finally, two model peptide hexamers (NNQQNY and VEALYL) composed of sequences that play key roles in amyloid fibril formation, are under investigation as prefibrillar aggregates (oligomer ions containing 2-12 monomers), with the goal of obtaining unique spectroscopic signatures of the early stages of interdigitized beta-sheet formation.
This research project impacts society at large by providing incisive experimental tests of important natural and synthetic structural scaffolds, which can aid theoretical development of next-generation quantum chemical, force field, spectroscopic, and dynamics methods. Specific targets touch on important biophysical problems. Proline-rich alpha-peptides are models for unstructured protein segments. Synthetic foldamers form unique structural scaffolds designed to interact with specific biological receptors of relevance to a wide range of biomedical and drug-discovery applications. The probable role of soluble prefibrillar oligomers in amyloid disease pathogenesis makes them important targets for detailed structural characterization.
