Sequence-specificity is critical for native protein structure and function, even among proteins that lack a highly ordered structure. While single chain polymeric nanoparticles have been widely studied to mimic chain compactness of disordered proteins, they lack sequence definition. Sequences can be optimized computationally to have protein-like compactness, but it remains challenging to correlate a 1D sequence with its 3D structure without experimental characterization. Herein we describe what factors influence hydrophobic collapse of macromolecules, specifically peptidomimetic peptoids consisting of a hydrophobic and a polar monomer. After split-and-pool synthesis of a library, the hydrophobic microenvironment of the peptoids is screened via a solvatochromic dye and subsequent sequence identification by tandem mass spectrometry. From each sequence, hydrophobic composition, blockiness, and sequence pattern are quantified. Efficacy of the immobilized screen is confirmed for select sequences by solution phase characterization. Understanding the variables (e.g. patterning) that lead a macromolecule to have protein-mimetic hydrophobic pockets will be beneficial for future work developing aqueous receptors.

Sequence-Dependent conformation of peptoids

ACS Spring 2022

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