4.4 Article

Deciphering the Mechanistic Basis for Perfluoroalkyl-Protein Interactions

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CHEMBIOCHEM
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WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202300159

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biophysics; fluorine; molecular assembly; perfluoroalkyl; proteins

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Fluorine has become important in protein design, altering their folding, stability, oligomerization, and bioactivity. Perfluorinated amphiphiles can noncovalently modify proteins, changing their conformation and facilitating their dispersion in fluorous phases. Through various approaches, we establish structure-activity relationships and explore their impact on protein dynamics and intracellular trafficking. This research could contribute to the rational design of fluorinated proteins, inform on potential toxicity of perfluoroalkyl substances, and aid in the development of fluorine-modified biologics for drug discovery and delivery applications.
Although rarely used in nature, fluorine has emerged as an important elemental ingredient in the design of proteins with altered folding, stability, oligomerization propensities, and bioactivity. Adding to the molecular modification toolbox, here we report the ability of privileged perfluorinated amphiphiles to noncovalently decorate proteins to alter their conformational plasticity and potentiate their dispersion into fluorous phases. Employing a complementary suite of biophysical, in-silico and in-vitro approaches, we establish structure-activity relationships defining these phenomena and investigate their impact on protein structural dynamics and intracellular trafficking. Notably, we show that the lead compound, perfluorononanoic acid, is 10(6) times more potent in inducing non-native protein secondary structure in select proteins than is the well-known helix inducer trifluoroethanol, and also significantly enhances the cellular uptake of complexed proteins. These findings could advance the rational design of fluorinated proteins, inform on potential modes of toxicity for perfluoroalkyl substances, and guide the development of fluorine-modified biologics with desirable functional properties for drug discovery and delivery applications.

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