Sequence Changes Modulate Peptoid Self-Association in Water

Amelia A Fuller,Christian J Jimenez,Jonathan Huber,Alberto Ortega,Kalli M Dowell,Kyra N Mccomas,Jose L Moreno,Anna L Calkins,Ella K Martinetto

doi:10.3389/fchem.2020.00260

Amelia A Fuller, Christian J Jimenez + Show 7 more

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https://doi.org/10.3389/fchem.2020.00260

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Journal: Frontiers in Chemistry	Publication Date: Apr 23, 2020
Citations: 8	License type: CC BY 4.0

Affiliation: Santa Clara University

Abstract

Peptoids, N-substituted glycine oligomers, are a class of diverse and sequence-specific peptidomimetics with wide-ranging applications. Advancing the functional repertoire of peptoids to emulate native peptide and protein functions requires engineering peptoids that adopt regular secondary and tertiary structures. An understanding of how changes to peptoid sequence change structural features, particularly in water-soluble systems, is underdeveloped. To address this knowledge gap, five 15-residue water-soluble peptoids that include naphthalene-functionalized side chains were designed, prepared, and subjected to a structural study using a palette of techniques. Peptoid sequence designs were based on a putative amphiphilic helix peptoid bearing structure-promoting (S)-N-(1-naphthylethyl)glycine residues whose self-association in water has been studied previously. New peptoid variants reported here include sequence changes that influenced peptoid conformational flexibility, functional group patterning (amphiphilicity), and hydrophobicity. Peptoid structures were evaluated and compared using circular dichroism spectroscopy, fluorescence spectroscopy, and size exclusion chromatography. Spectral data confirmed that sequence changes alter peptoids' degree of assembly and the organization of self-assembled structures in aqueous solutions. Insights gained in these studies will inform the design of new water-soluble peptoids with regular structural features, including desirable higher-order (tertiary and quaternary) structural features.

Highlights

IntroductionThe functions of most proteins rely on their ability to adopt complex folded structures that include intramolecular structural features (secondary or tertiary folds) and, in many cases, well-defined intermolecular contacts (quaternary structure)
The functions of most proteins rely on their ability to adopt complex folded structures that include intramolecular structural features and, in many cases, well-defined intermolecular contacts
Crude peptoids were subsequently purified by reverse-phase highperformance liquid chromatography (RP-HPLC) and identified by mass spectrometry

Summary

Introduction

The functions of most proteins rely on their ability to adopt complex folded structures that include intramolecular structural features (secondary or tertiary folds) and, in many cases, well-defined intermolecular contacts (quaternary structure). Peptoids that adopt regular secondary structures, including helices (Armand et al, 1998; Wu et al, 2001, 2003; Roy et al, 2017; Gimenez et al, 2018, 2019), sheets (Crapster et al, 2011), Sequence Changes Modulate Peptoid Self-Association and other regular structures (Gorske et al, 2017) have been described and applied. Oligomers with sterically bulky and/or electron-poor N-substituents generally favor the cis-amide bond (Gorske et al, 2009); this configuration promotes a peptoid helix secondary structure with three residues per turn and a helix pitch of 6 Å (Armand et al, 1998). Investigations into the contributions of both specific side chains and sequence ordering to peptoid secondary structure have begun to clarify sequence requirements for the predictive design of peptoids with helical structures (Wu et al, 2001; Shin et al, 2014)

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