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The Low-Energy Conformations of Gonadotropin-Releasing Hormone in Aqueous Solution

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Abstract

Using the chain-build-up method based on Empirical Conformational Energies of Peptides Program including solvation, we have computed, the low energy conformations of gonadotrpin-releasing hormone, GnRH, whose sequence is Pyro-Glu(PG)-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2. We have found 5,077 solvated conformations with conformational energies that were within 5 kcal/mole of that of the global minimum. These minima were found to occur in 802 distinct conformational classes of which 25 represented 70 % of the Boltzmann energy-weighted structures. Virtually all of these structures adopted bend conformations from Tyr 5-Leu 8, and 3,861 structures adopted bend conformations at residues 4–7. However, these structures differed significantly from one another, indicating that GnRH does not adopt a well-defined structure in aqueous solution consistent with the absence of a well-defined NMR structure of GnRH in water. A total of 300 of these structures were found to be superimposable on possible NMR structures for GnRH in DMSO with a combined statistical weight of 1.6 %. We found that Gly 6 adopts low energy “starred” states, e.g., C* and D*, that are energetically forbidden to l-amino acids but are low energy for d-amino acids, with a statistical weight of 43 %. This can explain why substitutions of l-amino acids for Gly 6 are known to inactivate GnRH while d-amino acid substitutions enhance its activity. Using these findings, in the accompanying manuscript, we compute the low energy conformations for the substituted GnRHs that enable inference of possible receptor-bound conformations.

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Abbreviations

GnRH:

Gonadotropin-releasing hormone

ECEPP:

Empirical Conformational Energies of Peptides Program

RMS:

Root mean square

PGL:

Pyro-glutamic acid

NOE:

Nuclear overhauser effect

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Acknowledgments

We wish to thank the Scientific Academic Computing Center, particularly Dr. Matthew Avitable and the University Hospital Computing Center of SUNY Downstate Medical Center for their excellent support for this project. We also acknowledge the support of the United States Department of Veteran Affairs and of the staff of the research service of the VA New York Harbor Health Care System for this project.

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Authors and Affiliations

  1. Department of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY, 11203, USA

    Matthew R. Pincus & Regina Monaco

  2. Department of Pathology and Laboratory Medicine, New York Harbor VA Medical Center, 800 Poly Place, Brooklyn, NY, 11209, USA

    Matthew R. Pincus & Regina Monaco

  3. Department of Pathology, Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA

    Jannie Woo

  4. Scientific Academic Computing Center, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY, 11203, USA

    Jack Lubowsky & Matthew J. Avitable

  5. Department of Biochemistry, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY, 11203, USA

    Robert P. Carty

  6. Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA

    Robert P. Carty

Authors
  1. Matthew R. Pincus
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  2. Jannie Woo
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  3. Regina Monaco
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  4. Jack Lubowsky
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  5. Matthew J. Avitable
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  6. Robert P. Carty
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Corresponding authors

Correspondence to Matthew R. Pincus or Robert P. Carty.

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Pincus, M.R., Woo, J., Monaco, R. et al. The Low-Energy Conformations of Gonadotropin-Releasing Hormone in Aqueous Solution. Protein J 33, 565–574 (2014). https://doi.org/10.1007/s10930-014-9589-3

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