02535nas a2200229   4500008004100000022001400041245009600055210006900151260000900220300001400229490000700243520174900250653000901999653002002008653003702028653002502065653002302090100002002113700002002133700002802153856012402181       2022                        eng d  a1948-719300aSynergistic and competitive lipid interactions in the serotonin1A receptor microenvironment0 aSynergistic and competitive lipid interactions in the serotonin1  cDEC   a3403-34150 v133 a<p>
	The interaction of lipids with G-protein-coupled receptors (GPCRs) has been shown to modulate and dictate several aspects of GPCR organization and function. Diverse lipid interaction sites have been identified from structural biology, bioinformatics, and molecular dynamics studies. For example, multiple cholesterol interaction sites have been identified in the serotonin1A receptor, along with distinct and overlapping sphingolipid interaction sites. How these lipids interact with each other and what is the resultant effect on the receptor is still not clear. In this work, we have analyzed lipid-lipid crosstalk at the receptor of the serotonin1A receptor embedded in a membrane bilayer that mimics the neuronal membrane composition by long coarse-grain simulations. Using a set of similarity coefficients, we classified lipids that bind at the receptor together as synergistic cobinding, and those that bind individually as competitive. Our results show that certain lipids interact with the serotonin1A receptor in synergy with each other. Not surprisingly, the ganglioside GM1 and cholesterol show a synergistic cobinding, along with the relatively uncommon GM1-phosphatidylethanolamine (PE) and cholesterol-PE synergy. In contrast, certain lipid pairs such as cholesterol and sphingomyelin appear to be in competition at several sites, despite their coexistence in lipid nanodomains. In addition, we observed intralipid competition between two lipid tails, with the receptor exhibiting increased interactions with the unsaturated lipid tails. We believe our work represents an important step in understanding the diversity of GPCR-lipid interactions and exploring synergistic cobinding and competition in natural membranes.</p>
10aGPCR10alipid crosstalk10aMartini coarse-grain simulations10aMembrane cholesterol10aneuronal membranes1 aMohole, Madhura1 aSengupta, Durba1 aChattopadhyay, Amitabha  uhttps://library.ncl.res.in/content/synergistic-and-competitive-lipid-interactions-serotonin1a-receptor-microenvironment02774nas a2200241   4500008004100000022001400041245015600055210006900211260000800280300001400288490000700302520190400309653001902213653001602232653000902248653003602257653001502293653002702308100002502335700002002360700002802380856012402408       2026                        eng d  a1948-719300aSpecificity and promiscuity of phosphoinositide lipid interactions with the serotonin1A receptor: insights from submillisecond coarse-grain simulations0 aSpecificity and promiscuity of phosphoinositide lipid interactio  cMAR  a1104-11140 v173 a<p>
	G protein-coupled receptors (GPCRs) are lipid-dependent membrane receptors that serve as important cell signaling hubs. Phosphoinositide (PIP) lipids represent an important class of anionic lipids that play vital roles in neuronal function and signaling. PIP lipids have been reported to modulate GPCR function, although the specificity and molecular details of the interactions are still not clear. An important GPCR in this context is the serotonin(1A) receptor, a neurotransmitter GPCR, which has been reported to interact with phosphatidylinositol 4-phosphate (PIP1) lipids. In this work, we computationally analyzed the specificity of the serotonin(1A) receptor-PIP lipid interactions using coarse-grain molecular dynamics simulations. Our results predict that four anionic lipid sites are present at the receptor surface, although the relative populations are dependent on the lipid type. PIP1 lipids exhibit the highest interaction at a charged cleft formed by transmembrane helices VI and VII. We observed electrostatic interactions at a cluster of charged residues (Arg341, Lys342, Lys345) and hydrophobic and aromatic interactions at residue Ile349 and Tyr402. In contrast, phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) lipids interact more with transmembrane helix IV. We observed that anionic phospholipids such as phosphatidylserine (PS) interact at these sites, although their occupancy at these sites is much reduced. By elucidating the molecular determinants of these interactions in silico, this study generates novel, testable hypotheses regarding the functional role of specific lipid-receptor contacts. Our work constitutes an important step in analyzing molecular signatures of phosphoinositide lipid-GPCR interactions in the overall context of diverse roles of phosphoinositides in neuronal function and signaling.</p>
10aanionic lipids10aCholesterol10aGPCR10aMARTINIcoarse-grain simulations10aPIP lipids10aserotonin(1A) receptor1 aNikte, Siddhanta, V.1 aSengupta, Durba1 aChattopadhyay, Amitabha  uhttps://library.ncl.res.in/content/specificity-and-promiscuity-phosphoinositide-lipid-interactions-serotonin1a-receptor