Sequence-Structure Relationships in Disordered Peptoids: A Toolkit for Design and Discovery

Broadly applicable design principles are necessary for the informed development of materials with desirable functions, such as cell penetration of a therapeutic or tunable enzyme-mimetic architecture. Understanding how a macromolecule’s primary sequence governs its conformational landscape is crucial for elucidating its function, yet these structural guidelines are still emerging for macromolecules with intrinsic disorder. Disordered macromolecules can adopt an ensemble of conformations, with no single predominant conformation. Examining the rich structural information encoded within a conformational ensemble can provide a fundamental understanding of how sequence dictates conformation, but these ensembles can present challenges for characterization. The work herein develops strategies for characterizing sequence–structure relationships in disordered oligomers to address the fundamental challenge of describing conformational ensembles and to subsequently enable functional materials improvement.Peptidomimetics, such as peptoids, are an ideal platform for connecting macromolecular sequence, structure, and function. First, we developed a model system of compositionally identical 20mer peptoids comprised of polar glycine and hydrophobic N-butylglycine to characterize using a suite of analytical techniques (Chapter 2). We introduce a facile colorimetric assay using immobilized sequences that leverages a solvatochromic probe, Reichardt’s dye, to visually reveal conformational trends consistent with experimental analysis and computational modeling. With these tools, we sampled a broad sequence space and created a high-throughput workflow that introduces a semi-automated sequencing protocol using MALDI-MS/MS and pioneers a generalizable sequence-structure algorithm (Chapter 3). Additionally, we employed dynamic covalent exchange to examine site-specific intramolecular interactions and intermolecular interactions with target carbohydrate molecules (Chapter 4). Furthermore, recommendations for utilizing mass spectrometry sequencing and copper-catalyzed click chemistry for macromolecular peptoid development are provided (Appendix A and Appendix B, respectively). These multifaceted approaches enhance our understanding of sequence–conformation relationships and offer a powerful toolkit for accelerating the discovery and expansion of advanced materials with precise conformational control.