Conformer-specific Spectroscopy and Isomerization Dynamics of Peptide and Synthetic Foldamer Helices

Purdue University, West Lafayette IN

Investigators

Abstract

Most biologically relevant molecules (for example, proteins and DNA) are large enough that they can take on many molecular shapes, dictated by a delicate balance of internal ("intramolecular") interactions and interactions with the surrounding solvent or other neighboring molecules. One of the common folding patterns (called "foldamers") of naturally occurring peptides and proteins are alpha-helices, held together by hydrogen bonds ("H-bonds") between the amino acid constituents of the protein. However, synthetic chemists are designing new amino acid building blocks that prefer other hydrogen bonding arrangements (called "synthetic foldamers"), including helices with a wide array of different hydrogen bonding patterns. In this project funded by the Chemical Structure Dynamics and Mechanism (CSDM-A) program of the Chemistry Division, Professor Timothy Zwier of Purdue University is using an array of laser-based spectroscopy methods to probe these helices and their interconversions in new ways. They take these molecules out of their natural environment by bringing them into the gas phase via laser desorption or electrospray ionization, and cool them to temperatures within a few degrees of absolute zero. In so doing, they probe the unique properties of each molecular conformation in the absence of solvent effects and without interference from the other conformations that may be present in the sample. Laser spectroscopic tools then probe the network of H-bonds in each helix, and reveal why some foldamers are preferred over others, and how much energy is needed to change from one foldamer form to another. This research project impacts society at large by providing incisive experimental tests of theoretical models that attempt to predict the shape and motions of molecules. Graduate and undergraduate students involved in the project are being trained for careers in high-technology industry, academia, and government laboratories. The Zwier research group continues to collaborate with predominantly undergraduate institutions (PUI, namely Profs. Stephen Drucker of UW-Eau Claire and Matt Kubasik at Fairfield University), thus enhancing the training of a broader range of undergraduate students, and provide unique career preparation opportunities for graduate students. The Zwier group is employing an array of laser-based spectroscopic methods for obtaining single-conformation spectra of gas-phase peptides in the infrared (IR) and ultraviolet (UV) spectral regions. Laser desorption and electrospray ionization are used to bring molecules or ions into the gas phase. Samples temperatures are brought below 10K via supersonic expansion or cryo-cooling. The gas-phase species are then interrogated using UV photo-fragmentation and UV-IR double-resonance techniques. Of particular interest are the inherent conformational preferences and unique vibrational and electronic absorptions of of natural and synthetic foldamer helices. Some of these molecules incorporate a molecular "tether" that "locks" the helix in place. On the other hand, conformational constraints synthesized into the molecular backbone may cause the molecule to fold in a specific way. The experimental spectra obtained are lending new insights into the mechanism and energy requirements for helix interconversion, and provide benchmark tests of the accuracy of state-of-the-art calculations (ab initio, density functional theory and semi-empirical force field calculations done on molecules in the absence of solvent). In addition to the benchmarking of theoretical models and the training of students, the findings of this research are advancing our understanding of synthetic foldamers, which may have applications in new materials and the treatment of disease. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.