Using X-ray Crystallography to Inform Foldamer Drug Design

Using X-ray Crystallography to Inform Foldamer Drug Design

Alvin Sherman Library

Foldamers are synthetic peptide oligomers that fold into well-defined three-dimensional structures, such as alpha-helices and beta-sheets. The goal of this project is to discover the solid-state confirmation of beta-amino acid foldamers that have potential as therapeutic molecules. This research represents an interdisciplinary collaboration between KAIST, a research university in South Korea, and NSU. We solved the single-crystal X-ray structures of two foldamers and then visualized their secondary structures and intermolecular contacts using Mercury. The first foldamer crystallized in the space group P2₁2₁2 and demonstrated a continuous alpha-helical secondary structure, with the residue side chains evenly distributed along the peptide backbone. Unlike the first foldamer, the second foldamer crystallized in the space group P1 and displayed a broken helical structure in consequence of an unusual amino acid residue that contains an internal double bond. This rigid residue reduced the flexibility of the backbone and prevented the formation of intramolecular hydrogen bonds conducive to helical folding. The broken structure positioned the residue side chains in a non-symmetric array, making this foldamer a poor drug candidate. This research demonstrates how X-ray crystallography enables structural insights into foldamer secondary structures, informs drug discovery, and provides a rational basis for designing protein-like small-molecule drugs.