title: Helix propensity of highly fluorinated amino acids.
abstract: Highly fluorinated amino acids have been used to stabilize helical proteins for potential application in various protein-based biotechnologies. To gain further insight into the effect of these highly fluorinated amino acids on helix formation exclusively, we measured the helix propensity of three highly fluorinated amino acids: (S)-5,5,5,5',5',5'-hexafluoroleucine (Hfl), (S)-2-amino-4,4,4-trifluorobutyric acid (Atb), and (S)-pentafluorophenylalanine (Pff). We have developed a short chemoenzymatic synthesis of Hfl with extremely high enantioselectivity (>99%). To measure the helix propensity (w) of the amino acids, alanine-based peptides were synthesized, purified, and investigated by circular dichroism spectroscopy (CD). On the basis of the CD data, the helix propensity of hydrocarbon amino acids can decrease up to 24-fold (1.72 kcal.mol-1.residue-1) upon fluorination. This difference in helix propensity has previously been overlooked in estimating the magnitude of the fluoro-stabilization effect (which has been estimated to be 0.32-0.83 kcal.mol-1.residue-1 for Hfl), resulting in a gross underestimation. Therefore, the full potential of the fluoro-stabilization effect should provide even more stable proteins than the fluoro-stabilized proteins to date.
authors.affiliation: Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260-3000, USA.
authors.forename: Hsien-Po
authors.initials: HP
authors.lastname: Chiu
authors.forename: Yuta
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Donald
authors.initials: D
authors.lastname: Gullickson
authors.forename: Raheel
authors.initials: R
authors.lastname: Ahmad
authors.forename: Bashkim
authors.initials: B
authors.lastname: Kokona
authors.forename: Robert
authors.initials: R
authors.lastname: Fairman
authors.forename: Richard P
authors.initials: RP
authors.lastname: Cheng
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D002942:Circular Dichroism; D005461:Fluorine / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D000596:Amino Acids; D010455:Peptides; D005461:Fluorine