6,556 research outputs found
Coarse-Grained MD Simulations Reveal Beta-Amyloid Fibrils of Various Sizes Bind to Interfacial Liquid-Ordered and Liquid-Disordered Regions in Phase Separated Lipid Rafts with Diverse Membrane-Bound Conformational States
The membrane binding behaviors of beta-amyloid fibrils, dimers to pentamers, from solution to lipid raft surfaces, were investigated using coarse-grained (CG) MD simulations. Our CG rafts contain phospholipid, cholesterol (with or without tail- or headgroup modifications), and with or without asymmetrically distributed monosialotetrahexosylganglioside (GM1). All rafts exhibited liquid-ordered (Lo), liquid-disordered (Ld), and interfacial Lo/Ld (Lod) domains, with domain sizes depending on cholesterol structure. For rafts without GM1, all fibrils bound to the Lod domains. Specifically, dimer fibrils bound exclusively via the C-terminal, while larger fibrils could bind via other protein regions. Interestingly, a membrane-inserted state was detected for a trimer fibril in a raft with tail-group modified cholesterol. For rafts containing GM1, fibrils bound either to the GM1-clusters, with numerous membrane-bound conformations, or to the non-GM1-containing-Lod domains via the C-terminal. Our results indicate beta-amyloid fibrils bind to Lod domains or GM1, with diversified membrane-bound conformations, in structurally heterogeneous lipid membranes
Scaling and Alpha-Helix Regulation of Protein Relaxation in a Lipid Bilayer
Protein conformation and orientation in the lipid membrane plays a key role in many cellular processes. Here we use molecular dynamics simulation to investigate the relaxation and C-terminus diffusion of a model helical peptide: beta-amyloid (Aβ) in a lipid membrane.We observed that after the helical peptide was initially half-embedded in the extracelluar leaflet of phosphatidylcholine (PC) or PC/cholesterol (PC/CHOL) membrane, the C-terminus diffused across the membrane and anchored to PC headgroups of the cytofacial lipid leaflet. In some cases, the membrane insertion domain of the Aβ was observed to partially unfold. Applying a sigmoidal fit to the process, we found that the characteristic velocity of the C-terminus, as it moved to its anchor site, scaled with θu â4/3, where θu is the fraction of the original helix that was lost during a helix to coil transition. Comparing this scaling with that of bead-spring models of polymer relaxation suggests that the C-terminus velocity is highly regulated by the peptide helical content, but that it is independent of the amino acid type. The Aβ was stabilized by the attachment of the positive Lys28 side chain to the negative phosphate of PC or 3β oxygen of CHOL in the extracellular lipid leaflet and of the C-terminus to its anchor site in the cytofacial lipid leaflet
Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics Simulations
The self-aggregation of tau, a microtubule-binding protein, has been linked to the onset of Alzheimerâs Disease. Recent studies indicate that the disordered tau aggregates, or oligomers, are more toxic than the ordered fibrils found in the intracellular neurofibrillary tangles of tau. At present, details of tau oligomer interactions with lipid rafts, a model of neuronal membranes, are not known. Using molecular dynamics simulations, the lipid-binding events, membrane-damage, and protein folding of tau oligomers on various lipid raft surfaces were investigated. Tau oligomers preferred to bind to the boundary domains (Lod) created by the coexisting liquid-ordered (Lo) and liquid-disordered (Ld) domains in the lipid rafts. Additionally, stronger binding of tau oligomers to the ganglioside (GM1) and phosphatidylserine (PS) domains, and subsequent protein-induced lipid chain order disruption and beta-sheet formation were detected. Our results suggest that GM1 and PS domains, located exclusively in the outer and inner leaflets, respectively, of the neuronal membranes, are specific membrane domain targets, whereas the Lod domains are non-specific targets, of tau oligomers binding to neurons. The molecular details of these specific and non-specific tau bindings to lipid rafts may provide new insights into understanding membrane-associated tauopathies leading to Alzheimerâs Disease
Design and Synthesis of New Acyl Urea Analogs as Potential Ď1R Selective Ligands
In search of synthetically accessible open-chain analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (Ď1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modeling the target compounds for drug-likeness, docking at Ď1R crystal structure 5HK1, and contrasting the lower energy molecular conformers with that of the receptor-embedded PD144418âa molecule we opined that our compounds could mimic pharmacologically. Synthesis of our acyl urea target compounds was achieved in two facile steps which involved first generating the N-(phenoxycarbonyl) benzamide intermediate and then coupling it with the appropriate aminesâweakly to strongly nucleophilic amines. Two potential leads (compounds 10 and 12, with respective in vitro Ď1R binding affinities of 2.18 and 9.54 ÎźM) emerged from this series. These leads will undergo further structure optimization with the ultimate goal of developing novel Ď1R ligands for testing in neurodegeneration models of Alzheimerâs disease (AD)
Characterization of 3D Voronoi Tessellation Nearest Neighbor Lipid Shells Provides Atomistic Lipid Disruption Profile of Protein Containing Lipid Membranes
Quantifying protein-induced lipid disruptions at the atomistic level is a challenging problem in membrane biophysics. Here we propose a novel 3D Voronoi tessellation nearest-atom-neighbor shell method to classify and characterize lipid domains into discrete concentric lipid shells surrounding membrane proteins in structurally heterogeneous lipid membranes. This method needs only the coordinates of the system and is independent of force fields and simulation conditions. As a proof-of-principle, we use this multiple lipid shell method to analyze the lipid disruption profiles of three simulated membrane systems: phosphatidylcholine, phosphatidylcholine/cholesterol, and beta-amyloid/phosphatidylcholine/cholesterol. We observed different atomic volume disruption mechanisms due to cholesterol and beta-amyloid. Additionally, several lipid fractional groups and lipid-interfacial water did not converge to their control values with increasing distance or shell order from the protein. This volume divergent behavior was confirmed by bilayer thickness and chain orientational order calculations. Our method can also be used to analyze high-resolution structural experimental data
Molecular Dynamics Simulations Reveal the Protective Role of Cholesterol in β-Amyloid Protein-Induced Membrane Disruptions in Neuronal Membrane Mimics
Interactions of β-amyloid (Aβ) peptides with neuronal membranes have been associated with the pathogenesis of Alzheimer\u27s disease (AD); however, the molecular details remain unclear. We used atomistic molecular dynamics (MD) simulations to study the interactions of Aβ40 and Aβ42 with model neuronal membranes. The differences between cholesterol-enriched and depleted lipid domains were investigated by the use of model phosphatidylcholine (PC) lipid bilayers with and without 40 mol % cholesterol. A total of 16 independent 200 ns simulation replicates were investigated. The surface area per lipid, bilayer thickness, water permeability barrier, and lipid order parameter, which are sensitive indicators of membrane disruption, were significantly altered by the inserted state of the protein. We conclude that cholesterol protects Aβ-induced membrane disruption and inhibits β-sheet formation of Aβ on the lipid bilayer. The latter could represent a two-dimensional (2D) seeding template for the formation of toxic oligomeric Aβ in the pathogenesis of AD
Acyl-Chain Mismatch Driven Superlattice Arrangements in DPPC/DLPC/Cholesterol Bilayers
Fluorescence and infrared spectroscopy and cholesterol oxidase activity were employed to investigate the effect of phosphatidylcholine (PC) acyl chain length mismatch on the lateral organizations of lipids in liquid-ordered dipalmitoyl-PC/dilauroyl-PC/cholesterol (DPPC/DLPC/CHOL) bilayers. Plots of steady-state fluorescence emission anisotropy of diphenylhexatriene (DPH) labeled PC (DPH-PC) embedded in the DPPC/DLPC/CHOL bilayers revealed significant peaks at several DPPC mole fractions (YDPPC) when the cholesterol mole fraction (XCHOL) was fixed to particular values. Analogously, the DPH-PC anisotropy peaked at several critical XCHOLâs when YDPPC was fixed. Acyl chain CâH and CâO vibrational peak frequencies of native PC as well as the activity of cholesterol oxidase also revealed dips and peaks at similar YDPPCâs. Importantly, most of the observed peaks/dips coincide with the critical mole fractions predicted by the Superlattice (SL) model. A three-dimensional map of DPH-PC anisotropy versus composition in the range 0.32 ⤠XCHOL ⤠0.50; 0.54 ⤠YDPPC ⤠0.72 revealed a prominent peak at (XCHOL, YDPPC) â (0.42, 0.64). This suggests a simultaneous presence of two different types of superlattices, one where cholesterol is the quest molecule in a PC host lattice and another where DPPC is the guest in the DLPC host lattice. Time-resolved measurements of DPH-PC fluorescence indicated the existence of an ordered, rotationally hindered environment of acyl chains at that âcriticalâ composition consistent with the existence of SL arrangements. We propose that beside CHOL/PC superlattices, DPPC, and DLPC as well tend to adopt regular SL-like lateral distributions relative to each other, presumably because the less hydrophobic DLPC molecule is slightly displaced toward the aqueous phase, thus allowing more room and mobility for the head groups of both DPPC and DLPC as well as for the acyl chain tails of DPPC. The parallel presence of two kinds of superlattices, that is, CHOL/PC-SL and DPPC/DLPC-SL as demonstrated here, has intriguing implications regarding lipid homeostasis of eukaryote membranes
Effects of Cholesterol in Stress-Related Neuronal DeathâA Statistical Analysis Perspective
The association between plasma cholesterol levels and the development of dementia continues to be an important topic of discussion in the scientific community, while the results in the literature vary significantly. We study the effect of reducing oxidized neuronal cholesterol on the lipid raft structure of plasma membrane. The levels of plasma membrane cholesterol were reduced by treating the intact cells with methyl-Ă-cyclodextrin (MĂCD). The relationship between the cell viability with varying levels of MĂCD was then examined. The viability curves are well described by a modified form of the empirical Gompertz law of mortality. A detailed statistical analysis is performed on the fitting results, showing that increasing MĂCD concentration has a minor, rather than significant, effect on the cellular viability. In particular, the dependence of viability on MĂCD concentration was found to be characterized by a ~25% increase per 1 ÎźM of MĂCD concentration
4,5-Dimethoxy-2-nitrobenzohydrazides and 1-(1-Benzylpiperidin-4-yl)ethan-1-ones as Potential Antioxidant/Cholinergic Endowed Small Molecule Leads
The objective of this research is to generate leads for developing our ultimate poly-active molecules with utility in central nervous system (CNS) diseases. Indeed, poly-active molecules capable of mitigating brain free radical damage while enhancing acetylcholine signaling (via cholinesterase inhibition) are still being sought for combating Alzheimerâs disease (AD). We differentiate âpoly-activeâ agents from âmulti-targetâ ones by defining them as single molecular entities designed to target only specific contributory synergistic pharmacologies in a disease. For instance, in AD, free radicals either initiate or act in synergy with other pharmacologies, leading to disease worsening. For this preliminary report, a total of 14 (i.e., 4,5-dimethoxy-2-nitrobenzohydrazide plus 1-(1-benzylpiperidin-4-yl)ethan-1-one) derivatives were synthesized and screened, in silico and in vitro, for their ability to scavenge free radicals and inhibit acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) enzymes. Overall, six derivatives (4a, 4d, 4e, 4f, 4g, 9b) exhibited potent (\u3e30%) antioxidant properties in the oxygen radical absorbance capacity (ORAC) assay. The antioxidant values were either comparable or more potent than the comparator molecules (ascorbic acid, resveratrol, and trolox). Only three compounds (4d, 9a, 9c) yielded modest AChE/BuChE inhibitions (\u3e10%). Please note that a SciFinder substance data base search confirmed that most of the compounds reported herein are new, except 9a and 9c which are also commercially available
Influences of dynamical disruptions on the evolution of pulsars in globular clusters
By comparing the physical properties of pulsars hosted by core-collapsed
(CCed) and non-core-collapsed (Non-CCed) globular clusters (GCs), we find that
pulsars in CCed GCs rotate significantly slower than their counterparts in
Non-CCed GCs. Additionally, radio luminosities at 1.4 GHz in CCed GCs are
higher. These findings are consistent with the scenario that dynamical
interactions in GCs can interrupt angular momentum transfer processes and
surface magnetic field decay during the recycling phase. Our results suggest
that such effects in CCed GCs are stronger due to more frequent disruptions of
compact binaries. This is further supported by the observation that both
estimated disruption rates and the fraction of isolated pulsars are
predominantly higher in CCed GCs.Comment: 9 pages, 8 figures, 3 tables, Accepted in MNRA
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