02684nas 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<p>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.</p>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-002198nas a2200241   4500008004100000022001400041245013700055210006900192260000800261300001200269490000800281520136100289653002801650653001501678653001001693653002501703653001501728100002201743700001801765700002001783700002801803856012501831       2018                        eng d  a0009-308400aMembrane-induced organization and dynamics of the N-terminal domain of chemokine receptor CXCR1: insights from atomistic simulations0 aMembraneinduced organization and dynamics of the Nterminal domai  cJAN  a142-1480 v2103 a<p>The CXC chemokine receptor 1 (CXCR1) is an important member of the G protein-coupled receptor (GPCR) family in which the extracellular N-terminal domain has been implicated in ligand binding and selectivity. The structure of this domain has not yet been elucidated due to its inherent dynamics, but experimental evidence points toward membrane-dependent organization and dynamics. To gain molecular insight into the interaction of the N-terminal domain with the membrane bilayer, we performed a series of microsecond time scale atomistic simulations of the N-terminal domain of CXCR1 in the presence and absence of POPC bilayers. Our results show that the peptide displays a high propensity to adopt a beta-sheet conformation in the presence of the membrane bilayer. The interaction of the peptide with the membrane bilayer was found to be transient in our simulations. Interestingly, a scrambled peptide, containing the same residues in a randomly varying sequence, did not exhibit membrane-modulated structural dynamics. These results suggest that sequence-dependent electrostatics, modulated by the membrane, could play an important role in folding of the N-terminal domain. We believe that our results reinforce the emerging paradigm that cellular membranes could be important modulators of function of G protein-coupled receptors such as CXCR1.</p>10aAll atom MD simulations10abeta-sheet10aCXCR110aMembrane interaction10aN-terminal1 aKharche, Shalmali1 aJoshi, Manali1 aSengupta, Durba1 aChattopadhyay, Amitabha  uhttps://library.ncl.res.in/content/membrane-induced-organization-and-dynamics-n-terminal-domain-chemokine-receptor-cxcr100457nas a2200133   4500008004100000245005100041210005100092300001100143100002000154700001800174700002000192700002800212856008300240       2020                        eng d00aMolecular determinants of GPCR oligomerization0 aMolecular determinants of GPCR oligomerization  a97-1081 aMohole, Madhura1 aKumar, Aditya1 aSengupta, Durba1 aChattopadhyay, Amitabha  uhttps://library.ncl.res.in/content/molecular-determinants-gpcr-oligomerization