Computational Insights into Prostaglandin E2 Ligand Binding and Activation of G-Protein-Coupled Receptors

G-protein coupled receptors (GPCRs) are eukaryotic integral membrane proteins that regulate signal transduction cascade pathways implicated in a variety of human diseases and are consequently of interest as drug targets. For this reason, it is of interest to investigate the way in which specific ligands bind and trigger conformational changes in the receptor during activation and how this in turn modulates intracellular signaling. In the present study, we investigate the way in which the ligand Prostaglandin E2 interacts with three GPCRs in the E-prostanoid family: EP1, EP2, and EP3. We examine information transfer pathways based on long-time scale molecular dynamics simulations using transfer entropy and betweenness centrality to measure the physical transfer of information among residues in the system. We monitor specific residues involved in binding to the ligand and investigate how the information transfer behavior of these residues changes upon ligand binding. Our results provide key insights that enable a deeper understanding of EP activation and signal transduction functioning pathways at the molecular level, as well as enabling us to make some predictions about the activation pathway for the EP1 receptor, for which little structural information is currently available. Our results should advance ongoing efforts in the development of potential therapeutics targeting these receptors.

Automated summary

In this study, the interaction between the ligand Prostaglandin E2 and three GPCRs in the E-prostanoid family (EP1, EP2, and EP3) was investigated using long-time scale molecular dynamics simulations. Transfer entropy and betweenness centrality were used to measure the information transfer pathways among residues involved in ligand binding. The results provide insights into the activation and signal transduction pathways of these receptors and contribute to the development of potential therapeutics targeting them.