Title
Deciphering the Mechanistic Basis for Perfluoroalkyl-Protein Interactions
Author
Lawanprasert, Atip, Janna N. Sloand, Mariangely González Vargas, Harminder Singh, Tomer Eldor, Michael A. Miller, Sopida Pimcharoen, Jian Wang, Scott M. Leighow, Justin R. Pritchard, Nikolay V. Dokholyan, and Scott H. Medina
Year
2023
Journal
ChemBioChem
Abstract
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 non-covalently 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 106 more potent in inducing non-native protein secondary structure in select proteins compared to the well-known helix inducer trifluoroethanol, as well as significantly enhances the cellular uptake of complexed proteins. These findings may 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.
Instrument
J-1500
Keywords
Biophysics,Fluorine,Molecular Assembly,Perfluoroalkyl,Protei