Theoretical Conformational Analysis of Oxytocin Molecule

Nikiforovich, Gregory V.; Leonova, V. I.; Galaktionov, S. G.; Chipens, G. I.

doi:10.1111/j.1399-3011.1979.tb01894.x

Cited by 31 publications

(3 citation statements)

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“…Similar results were confirmed from the conformational studies of OT in D 2 O and DMSO using NMR and molecular dynamics methods (Bhaskaran, Chuang, & Yu, 1992), and obtained the conformation similar to that of the crystal structure of deamino-oxytocin (Hruby, 1987;Wood et al, 1986). Other conformational studies (Kato, Endo, Fujiwara, & Nagayama, 1993;Liwo, Tempczyk, & Grzonka, 1989;Nikiforovich, Leonova, Galaktionov, & Chipens, 1979;Tarnowska et al, 1993) reported the OT conformation that is characterized by β-sheet-like structures in the N-terminal cyclic hexapeptide with a β-turn conformation at residues 3, 4 (in YIQNC segment), the best agreement with crystal structure of deaminooxytocin.…”

Section: Introductionsupporting

confidence: 87%

“…It has been shown that the residues 4, 5 in CYIQNC sequence play important roles as the central residues in the formation of β-turns in IQNC segment, as has been shown in our studies on the cyclic hexapeptide . Such a view is consistent with the comparative studies on the conformational characterization of a cyclic ring of OT (Lippens et al, 1993;Liwo et al, 1989;Lubecka et al, 2014;Nikiforovich et al, 1979;Ward et al, 1991). The possibility of existence of type-III β-turn at the residue 4, 5 in IQNC segment in the micelle-environment has also been reported (Rodziewicz-Motowidlo et al, 2008).…”

Section: Conformational Transitions In Cyiqnc Sequencesupporting

confidence: 66%

“…Though the past NMR data on the cyclic part of the OT and its analogs revealed a β-turn at residues 3, 4, the possibilities of the occurrence of other types of conformations in different environmental conditions have also been reported, such as a turn at residues 4, 5 (Lippens et al, 1993), a γ-turn at Gln 4 (Mosberg, Hruby, & Meraldi, 1981), β-turn at 2, 3 or 4, 5 (Nikiforovich et al, 1979;Liwo et al, 1989;Ward, Chen, Platt, & Robson, 1991) with a dynamic equilibrium between β-turns at residues 2, 3; 3, 4; and 4, 5 (Liwo et al, 1996). Recently, a type-IV β-turn was also reported to be observed at residues 3, 4 (YIQN segment) in the cyclic sequence -c[CYIQNC]-PIG-NH2 -of mesotocin (a homologous cyclic sequence of OT) in water (Sikorska & Rodzeiwicz-Motowidlo, 2008) as well as in SDS micelle (Rodziewicz-Motowidlo, Sikorska, Oleszczuk, & Czaplewski, 2008), with the possibility of existence of a β-turn of type I or type III at residues 4, 5 in 3-6 segment (IQNC) in SDS micelles environment.…”

Section: Introductionmentioning

confidence: 95%

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Conformations of a model cyclic hexapeptide, CYIQNC:¹H-NMR and molecular dynamics studies

Kulkarni

Ojha

2014

Journal of Biomolecular Structure and Dynamics

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Solution conformation of the cyclic hexapeptide sequence, [cyclo-S-Cys-Tyr-Ile-Gln-Asn-Cys-S] (CYIQNC) - a disulfide-linked fragment of a neurohypophyseal peptide hormone oxytocin (OT) - has been investigated by high-field one-dimensional (1D) and two-dimensional (2D) NMR spectroscopic methods and compared with the results obtained from computer simulation studies. (1)H-NMR results based on temperature dependence of amide proton chemical shifts and nuclear Overhauser effect indicate that peptide in solution populates different conformations, characterized by two fused β-turns. The segment Ile(3)-Gln(4)-Asn(5)-Cys(6) yields a preferred type-III β-turn at residues 4, 5 (HB, 3HN → 6CO), while the segment Cys(6), Cys(1)-Tyr(2)-Ile(3) exhibits inherently weaker, flexible β-turn either of type I/II'/III/half-turn at residues 1, 2 (HB, 6HN → 3CO). The computer simulation studies using a mixed protocol of distance geometry-simulated annealing followed by constrained minimization, restrained molecular dynamics, and energy minimization showed the possibility of existence of additional conformations with the hydrogen bonds, (a) 5HN → 3CO and (b) 2HN → 6CO. These results, therefore, indicate that the additional conformations obtained from both NMR and simulation studies can also be possible to the peptide. These additional conformations might have very small population in the solution and did not show their signatures in these conditions. These findings will be helpful in designing more analogs with modifications in the cyclic moiety of OT.

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Section: Introductionsupporting

confidence: 87%

Section: Conformational Transitions In Cyiqnc Sequencesupporting

confidence: 66%

Section: Introductionmentioning

confidence: 95%

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Conformations of a model cyclic hexapeptide, CYIQNC:¹H-NMR and molecular dynamics studies

Kulkarni

Ojha

2014

Journal of Biomolecular Structure and Dynamics

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Interaction of oxytocin with Ca2+: II. Proton magnetic resonance and molecular modeling studies of conformations of the hormone and its Ca2+ complex

1996

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Drastic changes in the CD and fluorescence spectra of oxytocin [cyclo(Cys1‐Tyr2‐Ile3‐Gln4‐Asn5‐Cys6)‐Pro7‐Leu8‐Gly9‐NH2] occur on binding Ca2+ in trifluoroethanol (Ananthanarayanan and Brimble, preceding paper). To further characterize the conformation of the Ca2+‐bound hormone, we carried out 1H‐nmr measurements in deuterated trifluoroethanol of oxytocin and its 1 : 1 Ca2+ complex. The one‐dimensional nmr data identified residues involved in Ca2+ binding and the extent of their perturbation on Ca2+ addition. The 3JNH‐CH coupling constants and two‐dimensional nuclear Overhauser effect (NOE) spectral cross peaks confirmed the helical nature of the Ca2+ complex deduced from CD data. Interproton distances in the free hormone and its Ca2+ complex were estimated from the respective NOE data. Apparent global minimum‐energy conformations of free and Ca2+ bound oxytocin were computed using the Monte Carlo with energy minimization protocol, with and without incorporating the NOE‐derived distance constraints. Taken together, our results show Ca2+ binding to oxytocin to be a two‐step process. The binding of the first Ca2+ brings the otherwise extended tail segment of oxytocin closer to the ring moiety so that it wraps around the cation. This causes the maximal extent of change in all the spectral parameters. The subsequent formation of the 2 : 1 Ca‐oxytocin complex results in the tail detaching itself away from the ring so as to bind the second Ca2+ ion. This leads to further spectral changes in the hormone molecule. The tail segment plays a major role in both steps. These observations may be useful in understanding the structural basis of oxytocin action. © 1997 John Wiley & Sons, Inc. Biopoly 40: 445–464, 1996

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

et al. 1998

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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.

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Theoretical Conformational Analysis of Oxytocin Molecule

Cited by 31 publications

References 28 publications

Conformations of a model cyclic hexapeptide, CYIQNC:¹H-NMR and molecular dynamics studies

Conformations of a model cyclic hexapeptide, CYIQNC:¹H-NMR and molecular dynamics studies

Interaction of oxytocin with Ca2+: II. Proton magnetic resonance and molecular modeling studies of conformations of the hormone and its Ca2+ complex

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

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Theoretical Conformational Analysis of Oxytocin Molecule

Cited by 31 publications

References 28 publications

Conformations of a model cyclic hexapeptide, CYIQNC:1H-NMR and molecular dynamics studies

Conformations of a model cyclic hexapeptide, CYIQNC:1H-NMR and molecular dynamics studies

Interaction of oxytocin with Ca2+: II. Proton magnetic resonance and molecular modeling studies of conformations of the hormone and its Ca2+ complex

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

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Product

Resources

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Conformations of a model cyclic hexapeptide, CYIQNC:¹H-NMR and molecular dynamics studies

Conformations of a model cyclic hexapeptide, CYIQNC:¹H-NMR and molecular dynamics studies