02357nas a2200265   4500008004100000022001400041245015900055210006900214260009200283300001200375490000700387520131600394653000901710653002501719653003401744653002701778100002201805700002301827700002001850700002101870700002001891700002201911700002801933856013001961       2015                        eng d  a0968-768800aDifferential dynamics of the serotonin(1A) receptor in membrane bilayers of varying cholesterol content revealed by all atom molecular dynamics simulation0 aDifferential dynamics of the serotonin1A receptor in membrane bi  a4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLANDbTAYLOR & FRANCIS LTDcMAY  a127-1370 v323 a<p>The serotonin(1A) receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target in neuropsychiatric disorders. The receptor has been shown to require membrane cholesterol for its organization, dynamics and function. Although recent work suggests a close interaction of cholesterol with the receptor, the structural integrity of the serotonin(1A) receptor in the presence of cholesterol has not been explored. In this work, we have carried out all atom molecular dynamics simulations, totaling to 3s, to analyze the effect of cholesterol on the structure and dynamics of the serotonin(1A) receptor. Our results show that the presence of physiologically relevant concentration of membrane cholesterol alters conformational dynamics of the serotonin(1A) receptor and, on an average lowers conformational fluctuations. Our results show that, in general, transmembrane helix VII is most affected by the absence of membrane cholesterol. These results are in overall agreement with experimental data showing enhancement of GPCR stability in the presence of membrane cholesterol. Our results constitute a molecular level understanding of GPCR-cholesterol interaction, and represent an important step in our overall understanding of GPCR function in health and disease.</p>10aGPCR10aMembrane cholesterol10amolecular dynamics simulation10aserotonin(1A) receptor1 aPatra, Swarna, M.1 aChakraborty, Sudip1 aShahane, Ganesh1 aPrasanna, Xavier1 aSengupta, Durba1 aMaiti, Prabal, K.1 aChattopadhyay, Amitabha  uhttps://library.ncl.res.in/content/differential-dynamics-serotonin1a-receptor-membrane-bilayers-varying-cholesterol-content-002774nas 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