A Molecular Dynamics Study of Interactions Between Amyloid-β Peptides and Model Lipid Membranes PDF Download
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Languages : en
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Author: Jun Zhao
Publisher:
ISBN:
Category : Amyloid
Languages : en
Pages : 280
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Biological membranes function as an essential barrier between living cells and their environments. The membrane associated peptides (MAPs) interact with membrane either to facilitate the molecules exchange between the environments and cytoplasm (e.g. cell-penetrating peptide), or to disturb the membrane (e.g. amyloid peptides and antimicrobial peptides). The structures and activity of these peptides are essential to understand the mechanisms and to screen the drug candidates. Thus, in this dissertation, the structure prediction and screening of MAPs were firstly performed in Chapter II, III, and IV. We developed a structures-screening program base on GBMV implicit-solvent evaluation and a structure population evaluation program by Monte Carlo simulation to search the aggregated structures of amyloid peptide hIAPP with dominant populations. Seven stacking-sandwich models and three the wrapping-cord models were determined, which can also serve as templates to present double- and triple-stranded helical fibrils via peptide elongation, explaining the polymorphism of amyloid oligomers and fibrils. Base on the predicted oligomeric structures, the mechanisms of amyloid toxicity can be studied. We further investigated the dynamic structures, ion conductivity, and membrane interactions of hIAPP pores in the DOPC bilayer using molecular dynamics simulations (Chapter V and VI). Our results suggested that loosely-associated [Beta]-structure motifs can be a general feature of toxic, unregulated channels. The process how MAPs adsorb on membrane and further penetrate across the membrane was futher evaluated by the transmembrane potential mean force (PMF). We constructed an effect platform including adaptive biasing force (ABF) method which accelerates the membrane penetration process, umbrella sampling method which effectively generates trans-membrane PMFs, and MARTINI coarse-grained force field to measure the free energy required to transfer the MAPs from bulk water phase to water-membrane interface, and further to bilayer interior (Chapter VII). The results implied that biological activity of antimicrobial peptides appeared to be closely related to their trans-membrane ability indicated by the PMF profiles. Moreover, due to the complicated components of cell membrane, it is better to simplify the interactions between MAP-membrane to MAP-artificial surfaces. Thus, in the last part of the dissertation, we further presented a series of exploratory molecular dynamics (MD) simulations to study the early adsorption and conformational change of amyloid peptide [Amyloid-beta] oligomers from dimer to hexamer on three different self-assembled monolayers (SAMs) (Chapter VIII). Within the timescale of MD simulations, the conformation, orientation, and adsorption of [Amyloid-beta] oligomers on the SAMs was determined by complex interplay among the size of [Amyloid-beta] oligomers, the surface chemistry of the SAMs, and the structure and dynamics of interfacial waters.
Author: Sidney A. Simon
Publisher: Academic Press
ISBN: 0080925855
Category : Science
Languages : en
Pages : 606
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This volume contains a comprehensive overview of peptide-lipid interactions by leading researchers. The first part covers theoretical concepts, experimental considerations, and thermodynamics. The second part presents new results obtained through site-directed EPR, electron microscopy, NMR, isothermal calorimetry, and fluorescence quenching. The final part covers problems of biological interest, including signal transduction, membrane transport, fusion, and adhesion. Key Features * world-renowned experts * state-of-the-art experimental methods * monolayers, bilayers, biological membranes * theoretical aspects and computer simulations * rafts * synaptic transmission * membrane fusion * signal transduction
Author: Shushan He
Publisher:
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Category :
Languages : en
Pages : 111
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The structure of cellular membranes gives rise to important biological phenomena, and understanding the (de)mixing behavior of multicomponent lipid bilayers is an important step toward unraveling the nature of spatial composition heterogeneities in cellular membranes and their role in biological function. In this dissertation we focus on the spatial organization and compositional heterogeneity of model membrane systems and their interaction with small, biologically relevant peptides. I employed both coarse-grained and atomistic molecular dynamics simulations to study the composition phase diagram of a quaternary mixture of phospholipids and cholesterol, as well as to sample the configurational space of peptide-membrane interactions. I investigate the mechanisms controlling membrane spatial heterogeneity and membrane protein interaction. This work yields important new insight into both the structural properties of lipid bilayer systems with spatial and compositional heterogeneity at vastly different length scales, which has prompted numerous publications in the field seeking for a plausible mechanism. This work will also provide perspectives on configurations of the PAP248-286 peptide upon interacting with membranes, which, despite its importance for human health, has not received as much attention from the research community as other amyloid-forming peptides. In this wide-open field such simulations will have significant scientific impact.
Author: E. Edward Bittar
Publisher: JAI Press(NY)
ISBN: 9780762301416
Category : Cell-mediated cytotoxicity
Languages : en
Pages : 0
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Cellular toxicology has entered a new era. No longer are we concerned only with necrotic cell death produced by severe, acute insult (often to multiple intracellular targets) leading to disruption of the cell membrane. New advances in molecular and cellular biology are allowing the dissection of mechanisms of cell death involving more subtle targets within the cell. Toxicology has been very important, not only in understanding the mechanisms, nature, and severity of toxicity and thereby helping in risk assessment, but toxicology has also played a very important role in helping to understand basic biological processes. Historically this has perhaps been most evident in the use of toxic agents to interfere with specific reactions in the body and hence help to dissect out the mechanisms of metabolic processes. For example, the use of chemical inhibitors was very important in understanding the process of oxidative phosphorylation, or the tricarboxylic acid cycle. More recent examples are seen herein where toxicology interfaces with, for example structural biology in the study of the cytoskeletal components and their interactions. Indirectly, an understanding of the mechanisms of endogenous protective systems also improves knowledge of basic cell biology. Toxic insult and manipulation of cell signalling and control mechanisms in cell growth and differentation also highlight how important the discipline of cell toxicity has been and will continue to be a major contributor to our understanding of basic issues in the biological and biomedical sciences. This book offers selected reviews of some of the principal molecular mechanisms of cell toxicity.
Author: Seongwon Kim
Publisher:
ISBN:
Category : Alzheimer's disease
Languages : en
Pages : 82
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Amyloid-beta peptides are implicated in the Alzheimer's disease (AD), an age-related neurodegenerative disorder. In this work, we study the dynamics of Abeta monomer and oligomers in water and interacting with cofactors such as naproxen or lipid monolayer. All-atom force field combined with fast implicit solvent model and replica exchange molecular dynamics is used to obtain exhaustive sampling of Abeta monomer and oligomer conformations in water. Similar methodology is used to study the interaction of Abeta dimer and naproxen. The antiaggregation effect and the utility of naproxen as pharmaceutical agent against AD are discussed. In an attempt to understand the Abeta-membrane interaction which is believed to be responsible for cell toxicity, we study the interaction of Abeta monomer and lipid monolayer. A new force field for DMPC monolayer consistent with CHARMM19+SASA model is presented. A reliable statistical analysis of Abeta monomer bound to DMPC monolayer demonstrates that membrane interaction profoundly perturbs the structures of both the peptide and lipid monolayer.
Author: Raz Jelinek
Publisher: John Wiley & Sons
ISBN: 3527634339
Category : Science
Languages : en
Pages : 431
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Addressing one of the biggest riddles in current molecular cell biology, this ground-breaking monograph builds the case for the crucial involvement of lipids and membranes in the formation of amyloid deposits. Tying together recent knowledge from in vitro and in vivo studes, and built on a sound biophysical and biochemical foundation, this overview brings the reader up to date with current models of the interplay between membranes and amyloid formation. Required reading for any researcher interested in amyloid formation and amyloid toxicity, and possible avenues for the prevention or treatment of neurodegenerative disorders. From the contents: * Interactions of Alpha-Synuclein with Lipids * Interaction of hIAPP and its Precursors with Membranes * Amyloid Polymorphisms: Structural Basis and Significance in Biology and Molecular Medicine * The Role of Lipid Rafts in Alzheimer's Disease * Alzheimer's Disease as a Membrane-Associated Enzymopathy of Beta-Amyloid Precursor Protein (APP) Secretases * Impaired Regulation of Glutamate Receptor Channels and Signaling Molecules by Beta-Amyloid in Alzheimer's Disease * Membrane Changes in BSE and Scrapie * Experimental Approaches and Technical Challenges for Studying Amyloid-Membrane Interactions and more
Author: Natasha S. Barteneva
Publisher: Humana
ISBN: 9781493933006
Category : Medical
Languages : en
Pages : 0
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This detailed volume for the first time explores techniques and protocols involving quantitative imaging flow cytometry (IFC), which has revolutionized our ability to analyze cells, cellular clusters, and populations in a remarkable fashion. Beginning with an introduction to technology, the book continues with sections addressing protocols for studies on the cell nucleus, nucleic acids, and FISH techniques using an IFC instrument, immune response analysis and drug screening, IFC protocols for apoptosis and cell death analysis, as well as morphological analysis and the identification of rare cells. Written for the highly successful Methods in Molecular Biology series, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Imaging Flow Cytometry: Methods and Protocols will be a critical source for all laboratories seeking to implement IFC in their research studies.
Author: Mingzhen Zhang
Publisher:
ISBN:
Category : Aggregation (Chemistry)
Languages : en
Pages : 195
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Amyloid aggregation have been implicated in the pathology of many neurodegenerative diseases, including prion disease, Alzheimer's disease (AD), type II diabetes (T2D), and Parkinson disease. Amyloid peptides undergo the nucleation-polymerization aggregation process, during which amyloid peptides experience structural conversions from unstructured monomers to critical nucleus, and eventually to amyloid fibrils containing dominant ß-sheet structures. Such common misfolding and aggregation characteristics, in some cases, drive cross-seeding interactions between amyloid peptides, which play a major role in the progression and transmission between the neurodegenerative diseases. In the experiments, the cross-seeding interactions between amyloid peptides including ß-amyloid (Aß)-islet amyloid peptides (IAPP), Aß-tau, Aß-prion, human IAPP-rat IAPP, and tau-synuclein amyloids have been extensively implicated. However, high-resolution evidence is still unavailable and little is known about how these two peptides interact with each other. In our research, we perform the multiscale molecular simulations to sysmetically study the cross-seeding interactions between different amyloid peptides at the atomic resolution, with the particular focus on the prediction of the atomic structures, the dynamic behavious in bulk and membrane enviroment, and the interface properties of the hIAPP-rIAPP and Aß-hIAPP cross-seeding assemblies. In Chapter I and II, we model and simulate different heteroassemblies formed by the amyloidogenic hIAPP and the nonamyloidogenic rIAPP peptides. The U-shaped hIAPP monomers and oligomers can interact with conformationally similar rIAPP to form stable complexes and to co-assemble into heterogeneous structures via the interfacial hydrogen bonds and hydrophobic contacts at ß-sheet regions. This work demonstrates the existence of cross-interactions between the two different IAPP peptides at the atomic level, providing an improved fundamental understanding of the cross-seeding of different amyloid sequences towards amyloid aggregation and toxicity mechanisms. In Chapter III, IV and V, we investigate the cross-seeding interactions between Aß and hIAPP using a combination of coarse-grained (CG) replica-exchange molecular dynamics (REMD), all-atom molecular dynamics (MD) simulations and Markov Chain Monte Carlo (MCMC) simulations. We for the first time obtain the full free energy landscape for Aß-hIAPP cross-seeding interactions, by which the atomic structure of Aß-hIAPP cross-seeding assembly is determined. Computational mutagenesis studies reveal that disruption of interfacial salt bridges largely disfavor the ß-sheet-to-ß-sheet association, highlighting the importance of salt bridges in the formation of cross-seeding assemblies. We also probe the behaviors of Aß-hIAPP cross-seeding assemblies on zwitterionic POPC and anionic POPC/POPG membranes, determining the specific orientations and demonstrating that electrostatic interactions are the major forces governing peptide-lipid interactions. This work confirms the cross-seeding interactions between Aß and hIAPP, explaining the potential pathological link between AD and T2D. The atomic insights into the cross-seeding intearctions between amyloid peptides obtained from this work are expected to improve the understanding of the amyloid peptides and inspire the peptide inhibitor design towards the neurodegenerative diseases.
Author: John J. Kremer
Publisher:
ISBN:
Category :
Languages : en
Pages : 238
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