DYNAMICS OF CIS TRANS ISOMERIZATION OF THE CYSTEINE(6)-PROLINE PEPTIDE-BONDS OF OXYTOCIN AND ARGININE VASOPRESSIN IN AQUEOUS AND METHANOL SOLUTIONS

The kinetics and thermodynamics of cis half arrow right over half arrow left trans isomerization by rotation around the Cys6-Pro peptide bond of oxytocin (OT) and arginine-vasopressin (AVP) were characterized in aqueous and methanol solutions. Isomerization rate constants were determined over a range of temperatures by the inversion-magnetization transfer NMR method, and isomerization equilibrium constants were determined from resonance intensities. Activation parameters were obtained from Eyring plots of the rate constants. The trans conformation is the more abundant for both OT and AVP, and the abundance of the trans conformation is larger in methanol than in aqueous solution. Equilibrium constants for cis half arrow right over half arrow left trans isomerization are 12 and 20 for OT and 15 and 25 for AVP in aqueous and methanol solutions, respectively. Rate constants for cis-to-trans and trans-to-cis interconversions are 4.2 x 10(-2) and 3.5 x 10(-3) s-1 for OT and 6.7 x 10(-2) and 4.6 X 10(-3) s-1 for AVP in aqueous solution at 25 OC. Rate constants for both cis-to-trans and trans-to-cis interconversions are significantly larger for both OT and AVP in methanol solution, which is consistent with interconversion via a mechanism involving a less polar transition state characterized by partial rotation around the C-N bond. Comparison of trans-to-cis interconversion rate constants for OT and AVP with those for smaller proline-containing peptides suggests that the trans conformations of OT and AVP are not stabilized by intramolecular interactions between the macrocyclic hexapeptide rings and the acyclic tripeptide tails.