The impact of pyrrolidine hydroxylation on the conformation of proline-containing peptides.
[structure: see text] A series of eight dipeptides of the general formula Ac-Phe-Pro-NHMe was synthesized and the thermodynamics of the cis --> trans isomerization about the central amide bond were studied by NMR. Pro* represents the following prolines: l-proline (Pro), l-trans-4-hydroxyproline (Hyp), l-cis-4-hydroxyproline (hyp), l-cis-4-methoxyproline (hyp[OMe]), l-trans-3-hydroxyproline (3-Hyp), l-cis-3-hydroxyproline (3-hyp), l-2,3-trans-3,4-cis-3,4-dihydroxyproline (DHP), and l-2,3-cis-3,4-trans-3,4-dihydroxyproline (dhp). The conformation of the pyrrolidine ring in each case is discussed in light of previous structural studies, analysis of potential stereoelectronic effects, and NMR data. Hydroxy substituents at C-4 have a greater impact on cis --> trans isomerization than analogous substituents at C-3 as a result of the intervening bond distances and bridging groups. The position of the equilibrium and its dependence on temperature are a reflection of both enthalpic and entropic factors, the latter being complicated in this study by an Ar-Pro interaction in the cis conformation. The substituents on the pyrrolidine ring determine the conformation of the five-membered ring, which in turn influences the strength of the Ar-Pro interaction, backbone dihedral angles, and the relative energy of the cis and trans species. The ultimate position of the equilibrium depends on a complex blend of steric, electronic, and conformational factors.
Taylor
Carol M
CM
Institute of Fundamental Sciences, Massey University, Private Bag 11-222, Palmerston North, New Zealand. C.M.Taylor@massey.ac.nz
Hardré
Renaud
R
Edwards
Patrick J B
PJ
D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry*; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D011392:Proline / Q000737:chemistry*; D011759:Pyrrolidines / Q000737:chemistry*; D013816:Thermodynamics
D004151:Dipeptides; D011759:Pyrrolidines; D011392:Proline; C032519:pyrrolidine