In a league of its own, fluorine has the potential to enable us to engineer biopolymers with highly desirable properties. However, the particular challenge in using it as a tool lies in our ability to juggle the interplay between the specific properties of the fluorinated building block and its responsiveness to the environment it is exposed to.<br/>Fluorine has been shown to impart often favorable but seldom predictable properties to peptides and proteins, a phenomenon that is caused by the nature of the fluorine atom and properties of the C-F bond. Up until about two decades ago the outcomes of fluorine modification of peptides and proteins were largely left to chance. Driven by the motivation to extend the application of the unique properties of the element fluorine from medicinal and agro chemistry to peptide and protein engineering we have established multiple peptide and protein models with different properties for the purpose of studying the consequences of fluorine substitution in the context of a protein environment. In general, the consequences of incorporating the C-F bond into a biopolymer can be attributed to two distinct yet related phenomena: 1) the fluorine substituent can directly engage in intermolecular interactions with its environment and/or 2) the other functional groups present in the molecule can be influenced by the electron withdrawing nature of this element (intramolecular) and in turn interact differently with their immediate environment (intermolecular). Also, we could show that not only the nature of the side chain but also its immediate environment determine the outcome of this substitution.<br/>We have especially been fascinated to observe that the difference of as subtle as one fluorine atom in the side chain of an amino acid can dramatically influence the key properties of peptides and proteins such as hydrophobicity, polarity and secondary structure propensity. These properties are crucial factors in peptide and protein engineering as they direct properties as important as proteolytic stability and folding, and thus impact protein function. One of our current projects studies the way in which not just biomolecules in the laboratory, but whole living organisms accommodate fluorine and this talk will introduce our first results of this endeavor.

Fluorine in peptide and protein engineering

255th National Meeting (2018)

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