Quantum Mechanical and NMR Studies of Ring Puckering and cis/trans-Rotameric Interconversion in Prolines and Hydroxyprolines

Abstract

Nuclear magnetic resonance (NMR) and quantum mechanical (QM) studies have been carried out for proline (Pro) containing peptides: N-acetyl-l-proline (AcProOH) and N-acetyl-4-hydroxy-l-proline (AcHypOH). Preliminary results of variable temperature NMR measurements for Gly-Pro-Gly-Gly (GPGG), Val-Ala-Pro-Gly (VAPG), and Ala-Pro-Gly-Trp amide acetate salt (APGW) are also reported. The effect of solvent (D(2)O, DMSO-d(6) and CD(3)CN) on the pyrrolidine ring conformation and cis/trans-rotamerisation along the amide bond preceding Pro was investigated by temperature dependent NMR followed by detailed transition state (TS) searches for both conformational equilibria using QM methods. The results revealed the energetic characteristics of the TS, which were in satisfactory agreement with NMR, and the corresponding TS geometries, which are not available from experiment. The most remarkable feature of the cis/trans-rotamerisation is that the amide nitrogen in AcProOH and AcHypOH adopts a tetrahedral geometry in the TS. Various HF, DFT, and MP2 calculations together with implicit solvation modeling were employed in order to identify the most suitable QM protocols for reliable predictions of the geometry and the relative energies of the conformations of Pro and Hyp containing peptides in aqueous solution. Solution NMR results were used for the verification of the reliability of the QM predictions. The results indicate that the MP2 calculations combined with implicit solvation models are reasonably accurate in reproducing NMR measured populations of four different conformations of either AcProOH or AcHypOH in different solvents, whereas HF and DFT B3LYP calculations were significantly less accurate.

The puckering free-energy surface of proline

“…The graphs are visualized using Chimera. 38 As an important and special feature of proline, the pyrrolidine ring puckering has been studied in detail, 4,[8][9][10][11][12][13][14][15][16][17] and proline's two preferred puckering states have been characterized very well. Usually, the pyrrolidine ring puckering is symbolized with two parameters-the pseudorotation phase angle and amplitude-that can be calculated either by the five ring-atom positions 18 or by the five endocyclic torsion angles χ j .…”

“…24 As to the QM calculations, Kang and co-workers have thoroughly studied the preferable proline conformations using the different QM calculations, 11,12,14,16,25 and in a recent work Kang and Byun have compared the various QM calculations in studying the conformations of alanine dipeptide and proline dipeptide in the gas phase and in water. 26 Aliev and co-workers have studied the proline conformations using several QM calculations, 17 and they have also compared the results of NMR, DFT, and the empirical force field calculations. 15 Sahai et al have studied the four forms proline conformations, differing in N-and C-terminals, using the QM methods calculated at three levels of theory.…”

Valence anions of N-acetylproline in the gas phase: Computational and anion photoelectron spectroscopic studies

“…2). Since N-AcPro may exist in several conformations, as demonstrated by Aliev et al in their conformational NMR studies, 21,22 "-endo-" and -exo-" are used to differentiate between the C γ -endo and C γ -exo ring conformers, respectively, (see Fig. 2).…”

“…Employing the results of the above mentioned conformational NMR studies 21,22 we generated and optimized, at the B3LYP/6-1++G(d,p) level, six neutral structures of NAcPro (see Fig. 2).…”

Proline puckering parameters for collagen structure simulations

“…Both PRO and HYP have the endocyclic ring structures that can pucker UP (positive χ 2 value, C γ exo conformation) or DOWN (negative χ 2 value, C γ endo conformation), which have been studied extensively. [3][4][5] It is found that PRO prefers the DOWN puckering at the Xaa position and HYP prefers the UP puckering at the Yaa position. 6,7 In the collagen model made of PRO-PRO-GLY triplets, prolines at the Xaa positions usually pucker DOWN and those at the Yaa positions usually pucker UP.…”