Relationship between proton–proton nmr coupling constants and substituent electronegativities. III. Conformational analysis of proline rings in solution using a generalized Karplus equation

Abstract

SynopsisThe relationship between published vicinal proton-proton coupling constants and the pseudorotation properties of the pyrrolidine ring in L-proline, 4-hydroxy-~-proline, 4-fluoro-L-proline, and several linear and cyclic model proline peptides is investigated. Compared to earlier studies, several important improvements are incorporated (1) a new empirical generalization of the classical Karplus equation is utilized, which allows a valid correction for the effects of electronegativity and orientation of substituents on 35HH; (2) an empirical correlation between proton-proton torsion angles and the pseudorotational parameters P and T, is derived; and (3) the best fit of the conformational parameters to the experimental coupling constants is obtained by means of a computerized iterative least-squares procedure. Two pseudorotation ranges were considered, classified as type N ( x 2 positive sign) and type S (XZ negative sign). The conformational equilibrium is fully described in terms of four geometrical parameters (PN, TN, Ps, 7s) and the equilibrium constant K . The present results indicate that, in general, the geometrical properties found in x-ray studies of proline and hydroxyproline residues are well preserved in solution. Several novel features are encountered, however. It is demonstrated that the proline ring occurs in a practically 1:l conformational equilibrium between well-defined N-and S-type forms. Introduction of an amide group at the C-terminal end has no observable effect on this equilibrium, but the formation of a peptide bond a t the imino nitrogen site results in a pronounced, but not exclusive, preference for an S-type form which is roughly 1.1 kcal/mol more stable than its N-type counterpart. The hydroxyproline ring system in neutral or acidic medium displays a pure N-type state, but N-acetylation results in the appearance of a minor (S-type) conformation. Cyclic proline dipeptides similarly exist in a biased conformational equilibrium. The major form (77-88%) corresponds to the N-type conformer observed in the solid state; the minor S-form has not been observed before. In contrast, cyclic hydroxyproline dipeptides display complete conformational purity. Ranges of endocyclic torsion angles deduced for the various classes of pyrrolidine derivatives in solution are presented. Each torsion appears confined to a surprisingly narrow range, comprising about 4'-8" in most cases. In all, the proline ring is far less "floppy" than hitherto assumed.

Conformers of Gaseous Proline

“…[6±8] NMR [9] and IR [10,11] spectroscopy) and theoretical (molecular mechanics, [8,12] perturbed configuration interaction with localized orbitals (PCILO), [13] and ab initio [12, 14±17] ) calculations. Nevertheless, no high-quality structural investigation of the parent amino acid proline, similar to those available for some smaller neutral amino acids such as glycine [18±20] and a-alanine, [21] has been performed prior to the present study.…”

Assessing and refining molecular dynamics simulations of proteins with nuclear magnetic resonance data

“…More complex relationships have also been proposed (Haasnoot et al 1979;Haasnoot et al 1981;Imai and Osawa 1990;Suardıaz et al 2007;Schmidt 2007). The constants A, B and C are generally estimated by fitting 3 J-values measured for molecules whose dihedral angle values are presumed to be known.…”

Conformation of the Dipeptide Cyclo(L-Pro-L-Pro) Monitored by the Nuclear Magnetic Resonance and Raman Optical Activity Spectra. Experimental and ab Initio Computational Study

“…Apparently, conformation I corresponds to that found by the X-ray in crystal 30 as well as to the N (North)-conformation obtained by the pseudorotation analysis of NMR data. 23,27 Conformation II, corresponding to the S (South) conformation obtained by NMR, was not observed in the crystalline state. Both conformations I and II possess a C 2 symmetry axis, while conformation III loses the symmetry and can be viewed as an intermediate state between the first two forms (see Figure 2).…”