Unraveling Foldamer Secondary Structure: A Computational Investigation of New Folding Oligomers

Fobe, Theodore L.

Graduate Thesis Or Dissertation

Unraveling Foldamer Secondary Structure: A Computational Investigation of New Folding Oligomers Public Deposited

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Citeable URL: https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/0r967538f

Abstract

Biology achieves an astounding range of functions from proteins and nucleic acids. In the pursuit of imitating the functional macromolecules seen in nature, researchers synthesized a new class of polymer materials called foldamers. Foldamers are linear polymers that readily fold into a distinct folded state in solution. The incorporation of different chemistries into the foldamer backbone allows researchers to create new folded secondary structures not observed in nature. Because of foldamers' ability to self-assemble into well-defined nano-scale structures, they are a promising candidate for use in molecular signaling, anti-viral and anti-fungal agents, biomimetic therapeutics, molecular sensors, and catalysis.

In this thesis, I explore and develop various computational methods to study foldamer molecules. In chapter 1, I present a thorough review of existing computational methods to study foldamer molecules. Since foldamers are similar to other well-studied biopolymers, such as proteins and nucleic acids, there is a large amount of overlap in computational methods used to study biopolymers and foldamers. In chapter 2, I apply a top-down modeling approach to study foldamers with a series of simple coarse-grained (CG) models. In these CG models, we explore the effects of several monomer characteristics effect on the secondary structure these CG models adopt. The effect of monomer characteristics on foldamer secondary structure in these generic models generalizes to all foldamer chemistries and can be used to select chemistry in new atomistic foldamers. In chapter 3, I use molecular simulations to identify secondary structure in a novel para-ortho-para-terphenyl foldamer chemistry. I find that partial helical motifs are stabilized, however, these motifs are unable to to form in series. In chapter 4, I continue the investigation of terphenyl foldamer chemistry and develop an enhanced sampling workflow that can identify secondary structures in a set of different terphenyl foldamer chemistry. Here, I use molecular simulations of short terphenyl oligomers to identify secondary structures in terphenyl molecules. Reconstructing the identified secondary structures in longer oligomers shows that longer oligomers are able to stabilize these secondary structure motifs.

The collection of work presented here exemplifies the usefulness of computational methods for studying new foldamer systems. In a field of study that has primarily been dominated by experimental synthesis and characterization over the past 20 years, computational methods offer an alternative approach to not only identify and characterize existing foldamer chemistries but also help guide the discovery of new foldamers.

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