The G protein-coupled receptors (GPCRs) are membrane receptors that play a central role in cell signaling and pharmacology. The interaction of lipids with GPCRs has been shown to modulate and dictate several aspects of GPCR organization and function. In this talk, we will discuss the diversity of lipid interaction sites that have been identified from molecular dynamics studies and compare to structural data. Using coarse-grain simulations, we identified several GPCR-lipid, in particular GPCR-cholesterol signatures and highlight the common and specific features. Further, using a set of similarity coefficients, we classify lipids that bind at the receptor together as synergistic co-binding, and those that bind individually as competitive. Not surprisingly, the ganglioside GM1 and cholesterol show a synergistic co-binding. In contrast, certain lipid pairs such as cholesterol and sphingomyelin appear to be in competition at several sites, despite their co-existence in lipid nanodomains. To quantify these interactions, we estimate the energetics and dynamics of lipid association. We show that lipids bind to the receptor with varying energetics of 1-4 kT, and timescales of 1-10 µs. Multi-exponential fitting of the contact probability suggests a three-step model, that we correlate with the annular, intermediate and non-annular sites. High barrier heights are estimated between the states that reduce the association/dissociation kinetics. The results highlight that GPCR-lipid interactions are driven by both thermodynamic interactions and the dynamical features of lipid binding.
About the Speaker:
Dr. Durba Sengupta is currently a scientist and Associate Professor (AcSIR) at the National Chemical Laboratory, Pune, India. She has been awarded a doctoral degree from the University of Heidelberg, Germany and subsequently joined the University of Groningen, Netherlands as a postdoctoral researcher. The main interest of her research group is computational biology, in particular multi-scale simulations. They have been able to identify the molecular mechanisms underlying membrane protein dynamics and protein-lipid interactions. She has published widely in internationally reputed journals, and has been invited to international conferences in biophysics and computational biology. Dr. Sengupta is an editor of J. Membr. Biol. (Springer Nature Press) and an editorial board member of Proc. India Nat. Sci. Ac.. and has guest edited special issues for several journals.