@article {48968,
	title = {Palmitoylation of the glucagon-like peptide-1 receptor modulates cholesterol interactions at the receptor-lipid microenvironment},
	journal = {Journal of Physical Chemistry B},
	volume = {127},
	year = {2023},
	month = {DEC },
	pages = {11000-11010},
	type = {Article},
	abstract = {<p>
	The G protein-coupled receptor (GPCR) superfamily of cell surface receptors has been shown to be functionally modulated by post-translational modifications. The glucagon-like peptide receptor-1 (GLP-1R), which is a drug target in diabetes and obesity, undergoes agonist-dependent palmitoyl tail conjugation. The palmitoylation in the C-terminal domain of GLP-1R has been suggested to modulate the receptor-lipid microenvironment. In this work, we have performed coarse-grain molecular dynamics simulations of palmitoylated and nonpalmitoylated GLP-1R to analyze the differential receptor-lipid interactions. Interestingly, the placement and dynamics of the C-terminal domain of GLP-1R are found to be directly dependent on the palmitoyl tail. We observe that both cholesterol and phospholipids interact with the receptor but display differential interactions in the presence and absence of the palmitoyl tail. We characterize important cholesterol-binding sites and validate sites that have been previously reported in experimentally resolved structures of the receptor. We show that the receptor acts like a conduit for cholesterol flip-flop by stabilizing cholesterol in the membrane core. Taken together, our work represents an important step in understanding the molecular effects of lipid modifications in GPCRs.</p>
},
	issn = {1520-6106},
	doi = {10.1021/acs.jpcb.3c05930},
	author = {Naglekar, Amit and Chattopadhyay, Amitabha and Sengupta, Durba}
}
@article {49361,
	title = {Probing the energy landscape of the lipid interactions of the serotonin 1A receptor},
	journal = {Biophysical Chemistry},
	volume = {313},
	year = {2024},
	month = {OCT},
	pages = {107289},
	type = {Article},
	abstract = {<p>
	G protein-coupled receptors (GPCRs) are lipid-regulated transmembrane proteins that play a central role in cell signaling and pharmacology. Although the role of membrane lipids in GPCR function is well established, the underlying GPCR-lipid interactions have not been thermodynamically characterized due to the complexity of these interactions. In this work, we estimate the energetics and dynamics of lipid association from coarse-grain simulations of the serotonin1A receptor embedded in a complex membrane. We show that lipids bind to the receptor with varying energetics of 1-4 kT, and timescales of 1-10 mu s. The most favorable energetics and longest residence times are observed for cholesterol, glycosphingolipid GM1, phosphatidylethanolamine (PE) and phosphatidylserine (PS) lipids. Multi-exponential fitting of the contact probability suggests distinct dynamic regimes, corresponding to ps, ns and mu s timescales, that we correlate with the annular, intermediate and nonannular lipid sites. The timescales of lipid binding correspond to high barrier heights, despite their relatively weaker energetics. Our results highlight that GPCR-lipid interactions are driven by both thermodynamic interactions and the dynamical features of lipid binding.</p>
},
	keywords = {GPCR-lipid interactions, Lipid energetics, Lipid residence time, Molecular dynamics simulations, Serotonin 1 a receptor},
	issn = {0301-4622},
	doi = {10.1016/j.bpc.2024.107289},
	author = {Mohole, Madhura and Naglekar, Amit and Sengupta, Durba and Chattopadhyay, Amitabha}
}
