Effect of Fluoro-Amino Acids on Protein Secondary Structure Stability Richard Cheng, Department of Chemistry, University at Buffalo, SUNY Buffalo, NY 14260-3000 The stability of enzymes catalysts for application in organic synthesis can be improved by incorporating fluorinated amino acids. This fluoro-stabilization effect has been attributed to hydrophobics, because the difference in hydrophobicity between Leu and Hfl (0.4 kcal·mol-1·residue-1) is similar to the change in overall helical protein stability upon substituting Leu with Hfl (0.32-0.83 kcal·mol-1·residue-1). This estimation of the fluoro-stabilization effect assumes that the helix propensities are the same for the two amino acids. We aim to measure the -helix and -sheet propensities of fluoro-amino acids. This would be useful for quantitatively predicting the effect of fluoro-amino acids on protein stability. We have measured the helix propensity of fluoro-amino acids such as Hfl, showing that helix propensity decreases significantly upon introducing fluorines. Our results show that Hfl is significantly less favorable than Leu for helix formation. Therefore, the fluoro-stabilization effect is larger than the previous estimation of 0.32-0.83 kcal·mol-1·residue-1 by 1.15 kcal·mol-1·residue-1 for Hfl. These results suggest that the fluoro-stabilization effect more than overcomes the less favorable helix propensity. Also, the fluoro-stabilization effect may be more than just hydrophobics, but may also include more specific interactions such as those involving the dipole moments of the trifluoromethyl groups. Furthermore, fluoro-amino acids such as Hfl may be more suitable in non-helical structures (i.e. -sheet) to realize the full potential of the fluoro-stabilization effect.