EXPLORATION OF THE CONFORMATIONAL SPACE OF OXYTOCIN AND ARGININE-VASOPRESSIN USING THE ELECTROSTATICALLY DRIVEN MONTE-CARLO AND MOLECULAR-DYNAMICS METHODS

Conformational analysis of the neurohypophyseal hormones oxytocin (OT) and arginine-vasopressin (A VP) has been carried out using two differ ent computational approaches and three force fields, namely by the Ele ctrostatically Driven Monte Carlo (EDMC) method, with the Empirical Co nformational Energy Program for Peptides (ECEPP/3) force field or with the ECEPP/3 force field plus a hydration-shell model, and by simulate d-annealing molecular dynamics with the Consistent Valence Force Field (CVFF). The low-energy conformations obtained for both hormones were classified using the minimal-tree clustering algorithm and characteriz ed according to the locations of beta-turns in the cyclic moieties. Ca lculations with the CVFF force field located conformations With a beta -turn at residues 3 and 4 as the lowest energy ones both for. OT and f or AVP. In the ECEPP/3 force field the lowest energy, conformation of OT contained a beta-turn at residues 2 and 3, conformations with this location of the turn being higher in energy for AVP. The latter differ ence can be attributed to the difference in the size of the side chain in position 3 of the sequences: the bulkier phenylalanine residue of AVP in combination with the bulky Tyr(2) residue hinders the formation of a turn at residues 2 and 3. Conformations of OT and AVP with a tur n at residues 3,4 were in the best agreement with the x-ray structures of deaminooxytocin and pressinoic acid (the cyclic moiety of vasopres sin), respectively and with the nmr-derived distance constraints. Gene rally, the low-energy conformations obtained with the hydration-shell model were in a better agreement with the experimental data than the c onformations calculated in vacuo. It was found, however, that the obta ined low-energy conformations do not satisfy all of the nmr-derived di stance constraints and the nuclear Overhauser effect pattern observed in nmr studies can be fully explained only by assuming a dynamic equil ibrium between conformations with beta-turns at residues 2,3, 3,4, and 4,5. The low-energy structures of OT with a beta-turn at residues 2,3 have the disulfide ring conformations close to the model proposed rec ently for a potent bicyclic antagonist of OT [M. D. Shenderovich et al . (1994) Polish Journal of Chemistry, Vol. 25, pp. 921-927], although the native hormone differs from the bicyclic analogue by the conformat ion of the C-terminal tripeptide. This finding confirms the hypothesis of different receptor-bound conformations of agonists and antagonists of OT. (C) 1996 John Wiley & Sons, Inc.