Dataset Information

Neutron Scattering Studies of the Interplay of Amyloid ? Peptide(1-40) and An Anionic Lipid 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol.

ABSTRACT: The interaction between lipid bilayers and Amyloid ? peptide (A?) plays a critical role in proliferation of Alzheimer's disease (AD). AD is expected to affect one in every 85 humans by 2050, and therefore, deciphering the interplay of A? and lipid bilayers at the molecular level is of profound importance. In this work, we applied an array of neutron scattering methods to study the structure and dynamics of A?(1-40) interacting 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) bilayers. In the structural investigations of lipid bilayer's response to A? binding, Small Angle Neutron Scattering and Neutron Membrane Diffraction revealed that the A? anchors firmly to the highly charged DMPG bilayers in the interfacial region between water and hydrocarbon chain, and it doesn't penetrate deeply into the bilayer. This association mode is substantiated by the dynamics studies with high resolution Quasi-Elastic Neutron Scattering experiments, showing that the addition of A? mainly affects the slower lateral motion of lipid molecules, especially in the fluid phase, but not the faster internal motion. The results revealed that A? associates with the highly charged membrane in surface with limited impact on the structure, but the altered membrane dynamics could have more influence on other membrane processes.

SUBMITTER: Rai DK

PROVIDER: S-EPMC4995599 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Publications

Neutron Scattering Studies of the Interplay of Amyloid β Peptide(1-40) and An Anionic Lipid 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol.

Rai Durgesh K DK Sharma Veerendra K VK Anunciado Divina D O'Neill Hugh H Mamontov Eugene E Urban Volker V Heller William T WT Qian Shuo S

Scientific reports 20160809

The interaction between lipid bilayers and Amyloid β peptide (Aβ) plays a critical role in proliferation of Alzheimer's disease (AD). AD is expected to affect one in every 85 humans by 2050, and therefore, deciphering the interplay of Aβ and lipid bilayers at the molecular level is of profound importance. In this work, we applied an array of neutron scattering methods to study the structure and dynamics of Aβ(1-40) interacting 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) bilayers. In the ...[more]

PMID: 27503057

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Project description:Polyethylene glycol (PEG) lipid nanoparticles (LNPs) spontaneously assemble in water, forming uniformly sized nanoparticles incorporating drugs with prolonged blood clearance compared to drugs alone. Previously, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycerol)-2000] (DSPE-PEG2000) and several drug adducts, including doxorubicin, were analyzed by a combination of physical and molecular dynamic (MD) studies. In this study, a complete chemical shift assignment of DSPE-PEG2000 plus or minus doxorubicin was achieved using nuclear magnetic resonance (NMR), one-dimensional selective nuclear Overhauser spectroscopy (1D-selNOESY), NOESY, correlation spectroscopy (COSY), total correlated spectroscopy (TOCSY), heteronuclear single quantum coherence (HSQC), and HSQC-TOCSY. Chemical shift perturbation, titration, relaxation enhancement, and NOESY analysis combined with MD reveal detailed structural information at the atomic level, including the location of doxorubicin in the micelle, its binding constant, the hydrophilic shell organization, and the mobility of the PEG2000 tail, demonstrating that NMR spectroscopy can characterize drug-DSPE-PEG2000 micelles with molecular weights above 180 kDa. The MD study revealed that an initial spherical organization led to a more-disorganized oblate structure in an aqueous environment and agreed with the NMR study in the details of the fine structure, in which methyl group(s) of the stearic acid in the hydrophobic core of the micelle are in contact with the phosphate headgroup of the lipid. Although the molecular size of the LNP drug complex is about 180 kDa, atomic resolution can be achieved by NMR-based methods that reveal distinct features of the drug-lipid interactions. Because many drugs have unfavorable blood clearance that may benefit from incorporation into LNPs, a thorough knowledge of their physical and chemical properties is essential to moving them into a clinical setting. This study provides an advanced basic approach that can be used to study a wide range of drug-LNP interactions.

Dataset Information

Neutron Scattering Studies of the Interplay of Amyloid ? Peptide(1-40) and An Anionic Lipid 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol.

Publications

Neutron Scattering Studies of the Interplay of Amyloid β Peptide(1-40) and An Anionic Lipid 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol.

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