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

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.

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-002684nas a2200229 4500008004100000022001400041245008900055210006900144260007300213300001400286490000900300520185000309653002802159653000902187653000902196653003102205653002502236653002602261100002002287700002802307856011902335 2015 eng d a0005-273600aMolecular dynamics simulations of GPCR-cholesterol interaction: an emerging paradigm0 aMolecular dynamics simulations of GPCRcholesterol interaction an aPO BOX 211, 1000 AE AMSTERDAM, NETHERLANDSbELSEVIER SCIENCE BVcSEP a1775-17820 v18483 a

G protein-coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across cell membranes and represent major targets in the development of novel drug candidates. Membrane cholesterol plays an important role in GPCR structure and function. Molecular dynamics simulations have been successful in exploring the effect of cholesterol on the receptor and a general consensus molecular view is emerging. We review here recent molecular dynamics studies at multiple resolutions highlighting the main features of cholesterol-GPCR interaction. Several cholesterol interaction sites have been identified on the receptor that are reminiscent of nonannular sites. These cholesterol hot-spots are highly dynamic and have a microsecond time scale of exchange with the bulk lipids. A few consensus sites (such as the CRAC site) have been identified that correspond to higher cholesterol interaction. Interestingly, high plasticity is observed in the modes of cholesterol interaction and several sites have been suggested to have high cholesterol occupancy. We therefore believe that these cholesterol hot-spots are indicative of `high occupancy sites' rather than `binding sites'. The results suggest that the energy landscape of cholesterol association with GPCRs corresponds to a series of shallow minima interconnected by low barriers. These specific interactions, along with general membrane effects, have been observed to modulate GPCR organization. Membrane cholesterol effects on receptor structure and organization, that in turn influences receptor cross-talk and drug efficacy, represent a new frontier in GPCR research. This article is part of a Special Issue entitled: Lipid-protein interactions. Guest Editors: Amitabha Chattopadhyay and jean-Marie Ruysschaert. (C) 2015 Elsevier B.V. All rights reserved.

10aCoarse-grain simulation10aCRAC10aGPCR10aLipid-receptor interaction10aMembrane cholesterol10aReceptor dimerization1 aSengupta, Durba1 aChattopadhyay, Amitabha uhttps://library.ncl.res.in/content/molecular-dynamics-simulations-gpcr-cholesterol-interaction-emerging-paradigm-002535nas 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

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.

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-microenvironment