Asymmetric syntheses of highly fluorinated amino acids and their effects on protein stability
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Highly fluorinated amino acids have been used to enhance protein stability. The reason has been attributed to higher hydrophobicity of fluorocarbons. However, the source of enhance stability from the increase in protein secondary or tertiary structure formation was unclear. Also the alternative factors other than hydrophobicity may involve in fluoro-stabilization. An efficient chemoenzymatic synthetic route was developed to produce ( S )-5,5,5,5',5',5'-hexafluoroleucine and ( S )-5,5,5',5'-tetrafluoroleucine (Qfl) with different side chain hydrophobicity and polarity. ( S )-Pentafluorophenylalanine and ( S )-2-amino-4,4,4-trifluorobutyric acid were also used to explore the effects of highly fluorinated amino acids on stability of α-helix, β-sheet, and helical bundle protein structures using Ala-based helical peptide, protein G B1 domain, and GCN4-p1 coiled coil, respectively. Highly fluorinated amino acids have lower helix propensity but higher sheet propensity than their corresponding hydrocarbon amino acids. GCN4-Qfl has higher overall stability than GCN4-Leu but Qfl has lower helix propensity than Leu, suggesting that enhanced stability of Qfl comes from the tertiary structure formation. In addition, this increased energy cannot be explained by hydrophobicity because Qfl is less hydrophobic than Leu, indicating that alternative factors such as dipolar interactions, hydrogen bonding, or side chain size could be involved in fluoro-stabilization.