Conformational analysis of L-prolines in water

The results of the ring conformational analysis Of L-proline, N-acetyl-L-proline, and trans-4-hydroxy-L-proline by NMR combined with calculations using density functional theory (DFT) and molecular dynamics (MD) are reported. Accurate values of H-1-H-1 J-couplings in water and other solvents have been determined. Using a two-site equilibrium model, the C-gamma-endo conformer of L- proline in water has been identified as intermediate between T-gamma(delta) [twist(C-gamma-endo, C-delta-exo)] and E-gamma [envelope(C-gamma-endo)] and the C-gamma-exo conformer as T-beta(y). Both conformers were equally populated at room temperature. The N-acetyl [cis-rotamer T-gamma(beta)(80%)/E-gamma(20%) and trans-rotamer T-gamma(beta)(61%)/E-gamma(39%)] and 4-hydroxy (E-gamma) derivatives showed significant changes in both the population and the geometries of the preferred ring confon-ners. The combination of NMR predicted populations with the DFT B3LYP/6-311+G(2d,p)/IEFPCM calculations proved successful, resulting in fairly accurate predictions of J-couplings. Simulations using MD were mostly in favor of the two-site equilibrium model between C-gamma-endo and C-gamma-exo conformers, similar to that used for the analysis of NMR J-couplings. Various force fields examined for MD simulations failed to reproduce the ring conformational geometries and populations Of L-proline in water accurately, while significantly better agreement with NMR was found for trans-N-acetyl-L-proline using GROMOS and AMBER force fields.