INDUCTIVE EFFECTS ON THE STRUCTURE OF PROLINE RESIDUES

4(S)-Hydroxyproline (Hyp) residues constitute about 10% of most forms of collagen, the most abundant protein in vertebrates. X-Ray diffracti on analysis was used to ascertain how the structure of proline residue s is affected by the inductive effect elicited by the hydroxyl group o f Hyp residues. N-Acetylproline methylester (1), N-acetyl-4(S)-hydroxy proline methylester (2) and N-acetyl-4(S)-fluoroproline methylester (3 ) were synthesized, and their crystalline structures were determined a t high resolution. The amide bond of crystalline 1 was in the cis conf ormation, which is the minor isomer in solution, and the pyrrolidine r ing of 1 had C-gamma-endo pucker. In crystalline 2 and 3 the amide bon ds were in the trans conformation, and the pyrrolidine rings had C-gam ma-exo pucker. The lengths of the bonds between sp(3)-hybridized carbo n atoms in the pyrrolidine ring were significantly shorter in 2 and 3 than in 1, as was predicted by ab initio molecular orbital calculation s at the RHF/3-21G level of theory. No significant change in bond leng th was observed in the other bonds of 1, 2 or 3. The pyramidylization of the nitrogen atom increased dramatically in the order: 1<2<3. Toget her, these results indicate that electron-withdrawing substituents in the 4-position of proline residues can have a significant influence on the structure of these residues. In particular, the change in pyramid ylization suggests that such substituents increase the sp(3)-character of the prolyl nitrogen atom and could thereby alter the rate of proly l peptide bond isomerization. (C) Munksgaard 1994.