Theoretical study of the interactions between peptide tyrosine tyrosine [PYY (1-36)], a newly identified modulator in type 2 diabetes pathophysiology, with receptors NPY1R and NPY4R

Abstract

Purpose

Diabetes mellitus is a common condition in the clinically obese. Bariatric surgery is one of the ways to put type 2 diabetes in remission. Recent findings propose the appetite-regulator peptide tyrosine tyrosine (PYY) as a therapeutic option for patients with type 2 diabetes. This novel gut hormone restores impaired insulin and glucagon secretion in pancreatic islets and is implicated in type 2 diabetes reversal after bariatric surgery. The current study elucidates the interactions between PYY and the NPY1R and NPY4R receptors using computational methods.

Methods

Protein structure prediction, molecular docking simulation, and molecular dynamics (MD) simulation were performed to elucidate the interactions of PYY with NPY1R and NPY4R.

Results

The predicted binding models of PYY-NPY receptors are in agreement with those described in the literature, although different interaction partners are presented for the C-terminal tail of PYY. Non-polar interactions are predicted to drive the formation of the protein complex. The calculated binding energies show that PYY has higher affinity for NPY4R (ΔGGBSA = −65.08 and ΔGPBSA = −87.62 kcal/mol) than for NPY1R (ΔGGBSA = −23.11 and ΔGPBSA = −50.56 kcal/mol).

Conclusions

Based on the constructed models, the binding conformations obtained from docking and MD simulation for both the PYY-NPY1R and PYY-NPY4R complexes provide a detailed map of possible interactions. The calculated binding energies show a higher affinity of PYY for NPY4R. These findings may help to understand the mechanisms behind the improvement of diabetes following bariatric surgery.

Graphical abstract

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Acknowledgements

YSC acknowledges the Fundamental Research Grant Scheme (FRGS/1/2018/STG05/USM/02/1; 203/CIPPM/6711680) of the Malaysia Ministry of Education. RR acknowledges support from the Mauritius Research Council, now Mauritius Research and Innovation Council (MRIC), under the Mauritius Diaspora Scheme, the Africa Oxford (AfOx) Initiative, and the Diabetes UK RD Lawrence Research Fellowship. NS acknowledges support from the Higher Education Commission (HEC) of Mauritius.

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Correspondence to Yee Siew Choong or Reshma Ramracheya or Ponnadurai Ramasami.

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Choong, Y.S., Lim, Y.Y., Soong, J.X. et al. Theoretical study of the interactions between peptide tyrosine tyrosine [PYY (1-36)], a newly identified modulator in type 2 diabetes pathophysiology, with receptors NPY1R and NPY4R. Hormones (2021). https://doi.org/10.1007/s42000-021-00278-2

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Keywords

  • PYY
  • NPY1R
  • NPY4R
  • Molecular dynamics
  • Binding energy