G protein coupled receptors (GPCRs) work as transmembrane signal transmitters through conformational change, rather than transporting matter across the membrane. The activation conformational change of GPCRs is driven by the binding of agonist ligands. Among the many endogenous agonist ligands are peptides, such as angiotensin, relaxin, neurotensin, and orexin. One differing factor between classic small molecules and peptides is flexibility. In the development of peptide-based drugs, there is a drive towards reducing degrees of freedom in order to increase binding affinity or allow for membrane permeability. We seek to show that in the pursuit of agonists, the strategy of eliminating degrees of freedom might result in antagonistic effects. Our group previously demonstrated1 that the flexibility of NTS 8-13 TYR11 Chi1 angle to be important in determining ligand efficacy, with loss of flexibility resulting in antagonistic behaviour. In the current study, we aim to use molecular dynamics to reveal how this flexibility results in GPCR activation as a cascade of conformational changes. We hope that our findings can be generalized into a cascade of events that is also applicable in the activation of other peptide binding GPCR systems.
1Bumbak, F., Thomas, T., Noonan-Williams, B. J., Vaid, T. M., Yan, F., Whitehead, A. R., ... & Scott, D. J. (2020). Conformational changes in tyrosine 11 of neurotensin are required to activate the neurotensin receptor 1. ACS pharmacology & translational science, 3(4), 690-705.