Yee Siew Choong1, Yee Ying Lim2, Jia Xin Soong2, Nandini Savoo3, Claudia Guida4, Lydia Rhyman3,5, Reshma Ramracheya6,7, Ponnadurai Ramasami8,9. 1. Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800, Penang, Malaysia. yeesiew@usm.my. 2. Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800, Penang, Malaysia. 3. Computational Chemistry Group, Department of Chemistry, Faculty of Science, University of Mauritius, Réduit 80837, Mauritius. 4. Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, OX3 7LJ, United Kingdom. 5. Department of Chemical Sciences, University of Johannesburg, Doornfontein, Johannesburg 2028, South Africa. 6. Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, OX3 7LJ, United Kingdom. reshma.ramracheya@ocdem.ox.ac.uk. 7. Pharmaceutical Operations, Centre International de Dévelopment Pharmaceutique, BioPark Mauritius, Socota Phoenicia, Phoenix 73408, Mauritius. reshma.ramracheya@ocdem.ox.ac.uk. 8. Computational Chemistry Group, Department of Chemistry, Faculty of Science, University of Mauritius, Réduit 80837, Mauritius. p.ramasami@uom.ac.mu. 9. Department of Chemical Sciences, University of Johannesburg, Doornfontein, Johannesburg 2028, South Africa. p.ramasami@uom.ac.mu.
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.
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.
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Authors: S H Jacobsen; S C Olesen; C Dirksen; N B Jørgensen; K N Bojsen-Møller; U Kielgast; D Worm; T Almdal; L S Naver; L E Hvolris; J F Rehfeld; B S Wulff; T R Clausen; D L Hansen; J J Holst; S Madsbad Journal: Obes Surg Date: 2012-07 Impact factor: 4.129
Authors: Claudia Guida; Sam D Stephen; Michael Watson; Niall Dempster; Pierre Larraufie; Thomas Marjot; Tamsin Cargill; Lisa Rickers; Michael Pavlides; Jeremy Tomlinson; Jeremy F L Cobbold; Chun-Mei Zhao; Duan Chen; Fiona Gribble; Frank Reimann; Richard Gillies; Bruno Sgromo; Patrik Rorsman; John D Ryan; Reshma D Ramracheya Journal: EBioMedicine Date: 2019-01-11 Impact factor: 8.143