Single-conformation spectroscopy in the complexity gap: Synthetic foldamers

William H. James, Purdue University

Abstract

A fully predictive model of the sequence-structure-function relationship is a primary goal of biophysical chemistry. In order to realize this goal, a quantitative understanding of all conformational minima, transition states, and isomerization pathways on a molecule’s potential energy surface must be achieved. This effort is hindered by the dramatic increase in complexity exhibited by proteins as the number of residues is increased (Levinthal’s Paradox). While the realization of a fully predictive model is far off, much can be learned about the potential energy surfaces of small sections of large proteins using an experimental approach that couples the power of laser spectroscopy and the isolated molecule environment of a supersonic jet expansion. With this in mind, the present work employs double resonance spectroscopic methods to obtain UV and IR single-conformation spectral signatures of jet-cooled, short synthetic foldamers, bringing to light intrinsic conformational propensities. The results herein highlight the flexible nature of α/β-peptide foldamers, while providing fundamental insight into the subtle changes in conformational behavior upon rearrangement of the order of the residues (αβ vs. βα) in the peptide backbone, changing the chirality of a single chiral center (L-Phe vs. D-Phe) in a pair of adjacent chiral centers, and including a conformationally constrained residue. Furthermore, foldamers have the potential to take up new secondary structural elements by virtue of having homologated peptide backbones. This profound difference allows foldamer molecules to access regions of Ramachandran space unavailable to natural peptides. The study of the prototypical γ-peptide Ac-γ2-hPhe-NHMe presented in this work, revealed circumstances which promote the formation of an intramolecular face-to-face amide stacked structure, a new secondary structural element. The pervasiveness of this interaction was examined through spectroscopic investigation of γ-peptide derivatives and the Ac-γ 2-hPhe-NHMe(H2O)1 complex. Finally, the development of mass-resolved infrared population transfer spectroscopy, an extension of fluorescence-detection based infrared-population transfer spectroscopy (previously developed in the Zwier Group), is presented. This method provides a quantitative, experimental measure of the relative abundances of individual conformational isomers in a supersonic expansion free from interference from sample impurities, thermal decomposition products, and solvent.

Degree

Ph.D.

Advisors

Zwier, Purdue University.

Subject Area

Physical chemistry

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