Electronic structure calculations of fluorohistidine isomers

Presented at the 248th National Meeting of the American Chemical Society (ACS) held in San Francisco, California on August 11, 2014.This work assesses the stability and NMR shifts of fluorinated amino acids in different solvents. We have considered the τ and π tautomers for both 2-fluorohistidine (2F-his) and 4-fluorohistidine (4F-his) corresponding to different sites of amine protonation on the imidazole ring. For this, solvents with different dielectric constant were chosen to study solvation effects on stability and spectroscopic quantities. Free energies, vibrational frequencies, and 13C NMR and 19F NMR chemical shifts were calculated for optimized geometries of the zwitterionic and protonated forms of each fluorohistidine isomer. We performed calculations with the COSMO solvation model using MP2 and DFT methods using Gaussian09 software. Fluorinated amino acids can play an important role in understanding protein-protein interactions, protein folding, and protein structure-function. For instance, fluorinated amino acids provide spectroscopic tags for structural and dynamical NMR studies. Furthermore, the chemical versatility of the imidazole ring leads to the presence of histidine in the active site of ~50% of the enzymes. Incorporation of a fluorine atom into position 2 (2F-his) or 4 (4F-his) of the imidazole ring of histidine lowers the pKa values of the imidazole ring by several units. In pH-dependent biological processes, these differences in pKa of fluorinated analogues assist in exploring the role of histidine. Our work provides a basis for interpreting spectroscopic signals and puts forward a foundation for future studies on the effect of electronegative fluorine atoms in biological systems