(360a) Molecular Modeling, Simulation, and Structure Determination of GLP1/GLP1R Complex for Type-2 Diabetes Conference: AIChE Annual MeetingYear: 2015Proceeding: 2015 AIChE Annual MeetingGroup: Engineering Sciences and FundamentalsSession: Molecular Simulation and Modeling of Complex Molecules II Time: Tuesday, November 10, 2015 - 12:30pm-12:50pm Authors: Yildirim, M., Texas A&M University Floudas, C. A., Princeton University Tamamis, P., TAMU Kieslich, C. A., Texas A&M University Diabetes and obesity pose a significant threat on the global public health, and subsequently economic prosperity. In 2014, according to the International Diabetes Federation's annual report, 1 out of every 12 persons has diabetes, and half of them are not aware. Type-2 diabetes accounts for 90% of the diagnosed diabetes in adults. Despite being a prevalent disease, type-2 diabetes could be successfully treated by targeting the three major metabolically-related peptide hormone receptors: Glucagon-like peptide-1 receptor (GLP1R), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors (GCGR). Designed peptide agonists could provide stimulation of insulin segregation, and establish glucose homeostasis by activating the receptor signaling to a certain extent depending on the potency. In order to engineer more effective agonist peptide hormones, knowledge on the binding and signaling mechanisms of the three key peptide-receptor complex structures is of utmost importance. The lack of experimental studies for the GLP1-GLP1R, GIP-GIPR, and glucagon-GCGR complex structures provides the motivation for elucidating these structures using computational methods. To this end, we have used our computational protocol, based on binding free energy calculations, and molecular dynamics simulations, which has successfully produced complex structures in remarkable agreement with experimental findings [1-4]. We delineate the functional role of important GLP1/GLP1R residues that are associated with binding and signaling based on our complex structure, and provide comparisons with available experimental information. This work provides significant biological insights into the signaling mechanism of GLP1R by GLP1, and paves the way for drug design studies towards the discovery of novel type-2 diabetes therapeutics. References  Tamamis, P.; Floudas, C. A. Molecular Recognition of CXCR4 by a Dual Tropic HIV-1 gp120 V3 Loop. Biophysical Journal 2013, 105 (6), 1502-1514.  Tamamis, P.; Floudas, C. A. Molecular Recognition of CCR5 by an HIV-1 gp120 V3 Loop. PLoS ONE 2014, 9 (4), e95767.  Tamamis, P.; Floudas, C. A. Elucidating a Key Component of Cancer Metastasis: CXCL12 (SDF-1α) Binding to CXCR4. Journal of Chemical Information and Modeling 2014, 54 (4), 1174-1188.  Tamamis, P.; Floudas, C. A. Elucidating a Key Anti-HIV-1 and Cancer-Associated Axis: The Structure of CCL5 (Rantes) in Complex with CCR5. Scientific Reports 2014, 4 (5447), 1-9.