Fluorine NMR chemical shifts from proteins containing fluorinated amino acids are usually dispersed over a wide range when the protein is in its native conformation. The shift dispersion essentially disappears when the protein is unfolded. Origins of the large protein structure-induced shielding effects are not clear, although they have been ascribed to electric field effects, short-range electron-electron interactions ("van der Waals" effects), and various local magnetic anisotropies. The present work explores the relative contributions of electric fields and short-range electronic interactions to fluorine shielding of 6-fluorotryptophan residues contained in the enzyme dihydrofolate reductase E. coli (DHFR), in binary complexes of this enzyme with NADPH and with methotrexate, and in a ternary complex with NADPH and methotrexate. Comparison of computed shielding effects to experimental data suggest an important role for short-range electronic interactions in determining fluorine shielding changes in these proteins and a lesser, but nonnegligible, contribution of electric fields and other anisotropies to observed shielding effects. However, the methods employed for calculation of fluorine shielding effects do not have great predictive power for this enzyme, contrary to what has been possible in other systems. The failure to obtain a clean diagnosis of shielding in this system may be a consequence of high conformational mobility.