Exploration of the conformational space of oxytocin and arginine-vasopressin using the electrostatically driven Monte Carlo and molecular dynamics methods

Abstract

Conformational analysis of the neurohypophyseal hormones oxytocin (OT) and arginine‐vasopressin (AVP) has been carried out using two different computational approaches and three force fields, namely by the Electrostatically Driven Monte Carlo (EDMC) method, with the Empirical Conformational Energy Program for Peptides (ECEPP/3) force field or with the ECEPP/3 force field plus a hydration‐shell model, and by simulated‐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 characterized according to the locations of β‐turns in the cyclic moieties. Calculations with the CVFF force field located conformations with a β‐turn at residues 3 and 4 as the lowest energy ones both for OT and for AVP. In the ECEPP/3 force field the lowest energy conformation of OT contained a β‐turn at residues 2 and 3, conformations with this location of the turn being higher in energy for AVP. The later difference 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 Tyr2 residue hinders the formation of a turn at residues 2 and 3. Conformations of OT and AVP with a turn at residues 3,4 were in the best agreement with the x‐ray structures of deaminooxytocin and pressinoic acid (the cyclic moiety of vasopressin), respectively, and with the nmr‐derived distance constraints. Generally, the low‐energy conformations obtained with the hydration‐shell model were in a better agreement with the experimental data than the conformations calculated in vacuo. It was found, however, that the obtained low‐energy conformations do not satisfy all of the nmr‐derived distance constraints and the nuclear Overhauser effect pattern observed in nmr studies can be fully explained only by assuming a dynamic equilibrium between conformations with β‐turns at residues 2.3, 3.4, and 4.5. The low‐energy structures of OT with a β‐turn at residues 2.3 have the disulfide ring conformations close to the model proposed recently 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 conformation of the C‐terminal tripeptide. This finding confirms the hypothesis of different receptor‐bound conformations of agonists and antagonists of OT. © 1996 John Wiley & Sons, Inc.

Conformation and dynamics of 8-Arg-vasopressin in solution

“…These saddle-like conformations with a strongly puckered ring and the β-turns mentioned above have been confirmed computationally as "low-energy conformations" inter alia by Liwo et al [27] via Monte Carlo and molecular dynamics (MD) simulations.…”

Structure and conformation of Arg8 vasopressin modified analogs

“…These bands are evidence of the presence of an additional turn structure and suggest that our SERS spectra reveal all of the known Raman fingerprints of AVP. This finding is supported by the earlier 2D NMR conformational studies of the native AVP in aqueous [47,48] and dimethylsulfoxide (DMSO) [49] solutions and theoretical calculation from AVP molecule in vacuo, [50,51] [52,53] The S-S stretching vibration for the GGG, TGG, and TGT conformations of the -CC-S-S-CC-linkage appears around 510, 525, and 540 cm −1 , respectively, where a -C-S-S-C-torsion angle of 90 • is represented as G and that of 180 • is represented in the T form.…”

Penetratin and derivatives acting as antifungal agents

“…The conformational space of each peptide was explored using the method previously employed by Liwo et al [47] that included the electrostatically driven Monte Carlo (EDMC) method [29]. Conformational energy was evaluated using the ECEPP/3 force field [48].…”