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  1. Article ; Online: Transition Networks Unveil Disorder-to-Order Transformations in A

    Schäffler, Moritz / Samantray, Suman / Strodel, Birgit

    International journal of molecular sciences

    2023  Volume 24, Issue 14

    Abstract: The aggregation of amyloid-β (Aβ) peptides, particularly of Aβ1-42, has been linked to the pathogenesis of Alzheimer's disease. In this study, we focus on the conformational change of Aβ1-42 in the presence of glycosaminoglycans (GAGs) and 1-palmitoyl-2- ... ...

    Abstract The aggregation of amyloid-β (Aβ) peptides, particularly of Aβ1-42, has been linked to the pathogenesis of Alzheimer's disease. In this study, we focus on the conformational change of Aβ1-42 in the presence of glycosaminoglycans (GAGs) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids using molecular dynamics simulations. We analyze the conformational changes that occur in Aβ by extracting the key structural features that are then used to generate transition networks. Using the same three features per network highlights the transitions from intrinsically disordered states ubiquitous in Aβ1-42 in solution to more compact states arising from stable β-hairpin formation when Aβ1-42 is in the vicinity of a GAG molecule, and even more compact states characterized by a α-helix or β-sheet structures when Aβ1-42 interacts with a POPC lipid cluster. We show that the molecular mechanisms underlying these transitions from disorder to order are different for the Aβ1-42/GAG and Aβ1-42/POPC systems. While in the latter the hydrophobicity provided by the lipid tails facilitates the folding of Aβ1-42, in the case of GAG there are hardly any intermolecular Aβ1-42-GAG interactions. Instead, GAG removes sodium ions from the peptide, allowing stronger electrostatic interactions within the peptide that stabilize a β-hairpin. Our results contribute to the growing knowledge of the role of GAGs and lipids in the conformational preferences of the Aβ peptide, which in turn influences its aggregation into toxic oligomers and amyloid fibrils.
    MeSH term(s) Humans ; Glycosaminoglycans ; Amyloid beta-Peptides/chemistry ; Alzheimer Disease ; Molecular Dynamics Simulation ; Amyloid/chemistry ; Peptide Fragments/chemistry
    Chemical Substances Glycosaminoglycans ; Amyloid beta-Peptides ; Amyloid ; Peptide Fragments
    Language English
    Publishing date 2023-07-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms241411238
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  2. Article ; Online: The Effects of Different Glycosaminoglycans on the Structure and Aggregation of the Amyloid-β (16-22) Peptide.

    Samantray, Suman / Strodel, Birgit

    The journal of physical chemistry. B

    2021  Volume 125, Issue 21, Page(s) 5511–5525

    Abstract: Aggregates of the amyloid-β (Aβ) peptide are implicated as a causative substance in Alzheimer's disease. Molecular dynamics simulations provide valuable contributions for elucidating the conformational transitions of monomeric and aggregated forms of Aβ ... ...

    Abstract Aggregates of the amyloid-β (Aβ) peptide are implicated as a causative substance in Alzheimer's disease. Molecular dynamics simulations provide valuable contributions for elucidating the conformational transitions of monomeric and aggregated forms of Aβ be it in solution or in the presence of other molecules. Here, we study the effects of four different glycosaminoglycans (GAGs), three sulfated ones and a nonsulfated one, on the aggregation of Aβ
    MeSH term(s) Amyloid ; Amyloid beta-Peptides ; Glycosaminoglycans ; Peptide Fragments ; Protein Conformation, beta-Strand
    Chemical Substances Amyloid ; Amyloid beta-Peptides ; Glycosaminoglycans ; Peptide Fragments
    Language English
    Publishing date 2021-05-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1520-5207
    ISSN (online) 1520-5207
    DOI 10.1021/acs.jpcb.1c00868
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  3. Article ; Online: Effect of the air-water interface on the conformation of amyloid beta.

    Samantray, Suman / Cheung, David L

    Biointerphases

    2020  Volume 15, Issue 6, Page(s) 61011

    Abstract: It has long been recognized that liquid interfaces, such as the air-water interface (AWI), can enhance the formation of protein fibrils. This makes liquid interfaces attractive templates for fibril formation but fully realizing this requires knowledge of ...

    Abstract It has long been recognized that liquid interfaces, such as the air-water interface (AWI), can enhance the formation of protein fibrils. This makes liquid interfaces attractive templates for fibril formation but fully realizing this requires knowledge of protein behavior at interfaces, which is currently lacking. To address this, molecular dynamics simulation is used to investigate fragments of amyloid beta, a model fibril forming protein, at the air-water interface. At the air-water interface, the enrichment of aggregation-prone helical conformations provides a mechanism for the enhancement of fibrillation at interfaces. The conformational ensemble at the air-water interface was also considerably reduced compared to bulk solution due to the tendency of hydrophobic side chains partitioning into the air restricting the range of conformations. Little overlap between the conformational ensembles at the AWI and in the bulk solution was found, suggesting that AWI induces the formation of a different set of structures compared to bulk solution. The smaller Aβ(16-22) and Aβ(25-35) fragments show an increase in the propensity for an ordered secondary structure at the air-water interface but with a increased propensity for turn over other motifs, illustrating the importance of intra-protein interactions for stabilizing helical and extended conformations.
    MeSH term(s) Air ; Algorithms ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/metabolism ; Hydrogen Bonding ; Peptide Fragments/chemistry ; Peptide Fragments/metabolism ; Protein Conformation, alpha-Helical ; Water/chemistry
    Chemical Substances Amyloid beta-Peptides ; Peptide Fragments ; amyloid beta-protein (10-40) ; amyloid beta-protein (16-22) ; amyloid beta-protein (25-35) ; Water (059QF0KO0R)
    Language English
    Publishing date 2020-12-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2234510-3
    ISSN 1559-4106 ; 1934-8630
    ISSN (online) 1559-4106
    ISSN 1934-8630
    DOI 10.1116/6.0000620
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  4. Article ; Online: The Influences of Sulphation, Salt Type, and Salt Concentration on the Structural Heterogeneity of Glycosaminoglycans.

    Samantray, Suman / Olubiyi, Olujide O / Strodel, Birgit

    International journal of molecular sciences

    2021  Volume 22, Issue 21

    Abstract: The increasing recognition of the biochemical importance of glycosaminoglycans (GAGs) has in recent times made them the center of attention of recent research investigations. It became evident that subtle conformational factors play an important role in ... ...

    Abstract The increasing recognition of the biochemical importance of glycosaminoglycans (GAGs) has in recent times made them the center of attention of recent research investigations. It became evident that subtle conformational factors play an important role in determining the relationship between the chemical composition of GAGs and their activity. Therefore, a thorough understanding of their structural flexibility is needed, which is addressed in this work by means of all-atom molecular dynamics (MD) simulations. Four major GAGs with different substitution patterns, namely hyaluronic acid as unsulphated GAG, heparan-6-sulphate, chondroitin-4-sulphate, and chondroitin-6-sulphate, were investigated to elucidate the influence of sulphation on the dynamical features of GAGs. Moreover, the effects of increasing NaCl and KCl concentrations were studied as well. Different structural parameters were determined from the MD simulations, in combination with a presentation of the free energy landscape of the GAG conformations, which allowed us to unravel the conformational fingerprints unique to each GAG. The largest effects on the GAG structures were found for sulphation at position 6, as well as binding of the metal ions in the absence of chloride ions to the carboxylate and sulphate groups, which both increase the GAG conformational flexibility.
    MeSH term(s) Carbohydrate Conformation ; Carbohydrate Sequence ; Chondroitin Sulfates/chemistry ; Chondroitin Sulfates/metabolism ; Glycosaminoglycans/chemistry ; Glycosaminoglycans/metabolism ; Heparitin Sulfate/chemistry ; Heparitin Sulfate/metabolism ; Humans ; Hyaluronic Acid/chemistry ; Hyaluronic Acid/metabolism ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Molecular Dynamics Simulation ; Molecular Structure ; Potassium Chloride/chemistry ; Sodium Chloride/chemistry ; Sulfates/chemistry
    Chemical Substances Glycosaminoglycans ; Sulfates ; Sodium Chloride (451W47IQ8X) ; Potassium Chloride (660YQ98I10) ; Hyaluronic Acid (9004-61-9) ; Chondroitin Sulfates (9007-28-7) ; Heparitin Sulfate (9050-30-0)
    Language English
    Publishing date 2021-10-26
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms222111529
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  5. Article ; Online: Different Force Fields Give Rise to Different Amyloid Aggregation Pathways in Molecular Dynamics Simulations.

    Samantray, Suman / Yin, Feng / Kav, Batuhan / Strodel, Birgit

    Journal of chemical information and modeling

    2020  Volume 60, Issue 12, Page(s) 6462–6475

    Abstract: The progress toward understanding the molecular basis of Alzheimers's disease is strongly connected to elucidating the early aggregation events of the amyloid-β (Aβ) peptide. Molecular dynamics (MD) simulations provide a viable technique to study the ... ...

    Abstract The progress toward understanding the molecular basis of Alzheimers's disease is strongly connected to elucidating the early aggregation events of the amyloid-β (Aβ) peptide. Molecular dynamics (MD) simulations provide a viable technique to study the aggregation of Aβ into oligomers with high spatial and temporal resolution. However, the results of an MD simulation can only be as good as the underlying force field. A recent study by our group showed that none of the common force fields can distinguish between aggregation-prone and nonaggregating peptide sequences, producing a similar and in most cases too fast aggregation kinetics for all peptides. Since then, new force fields specially designed for intrinsically disordered proteins such as Aβ were developed. Here, we assess the applicability of these new force fields to studying peptide aggregation using the Aβ
    MeSH term(s) Amyloid ; Amyloid beta-Peptides ; Intrinsically Disordered Proteins ; Kinetics ; Molecular Dynamics Simulation ; Peptide Fragments
    Chemical Substances Amyloid ; Amyloid beta-Peptides ; Intrinsically Disordered Proteins ; Peptide Fragments
    Language English
    Publishing date 2020-11-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.0c01063
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1230: Show issues Location:
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  6. Article: Thermodynamics and kinetics of the amyloid-β peptide revealed by Markov state models based on MD data in agreement with experiment.

    Paul, Arghadwip / Samantray, Suman / Anteghini, Marco / Khaled, Mohammed / Strodel, Birgit

    Chemical science

    2021  Volume 12, Issue 19, Page(s) 6652–6669

    Abstract: The amlyoid-β peptide (Aβ) is closely linked to the development of Alzheimer's disease. Molecular dynamics (MD) simulations have become an indispensable tool for studying the behavior of this peptide at the atomistic level. General key aspects of MD ... ...

    Abstract The amlyoid-β peptide (Aβ) is closely linked to the development of Alzheimer's disease. Molecular dynamics (MD) simulations have become an indispensable tool for studying the behavior of this peptide at the atomistic level. General key aspects of MD simulations are the force field used for modeling the peptide and its environment, which is important for accurate modeling of the system of interest, and the length of the simulations, which determines whether or not equilibrium is reached. In this study we address these points by analyzing 30-μs MD simulations acquired for Aβ40 using seven different force fields. We assess the convergence of these simulations based on the convergence of various structural properties and of NMR and fluorescence spectroscopic observables. Moreover, we calculate Markov state models for the different MD simulations, which provide an unprecedented view of the thermodynamics and kinetics of the amyloid-β peptide. This further allows us to provide answers for pertinent questions, like: which force fields are suitable for modeling Aβ? (a99SB-UCB and a99SB-ILDN/TIP4P-D); what does Aβ peptide really look like? (mostly extended and disordered) and; how long does it take MD simulations of Aβ to attain equilibrium? (at least 20-30 μs). We believe the analyses presented in this study will provide a useful reference guide for important questions relating to the structure and dynamics of Aβ in particular, and by extension other similar disordered proteins.
    Language English
    Publishing date 2021-04-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2559110-1
    ISSN 2041-6539 ; 2041-6520
    ISSN (online) 2041-6539
    ISSN 2041-6520
    DOI 10.1039/d0sc04657d
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  7. Article ; Online: Molecular simulations of IDPs: From ensemble generation to IDP interactions leading to disorder-to-order transitions.

    Fatafta, Hebah / Samantray, Suman / Sayyed-Ahmad, Abdallah / Coskuner-Weber, Orkid / Strodel, Birgit

    Progress in molecular biology and translational science

    2021  Volume 183, Page(s) 135–185

    Abstract: Intrinsically disordered proteins (IDPs) lack a well-defined three-dimensional structure but do exhibit some dynamical and structural ordering. The structural plasticity of IDPs indicates that entropy-driven motions are crucial for their function. Many ... ...

    Abstract Intrinsically disordered proteins (IDPs) lack a well-defined three-dimensional structure but do exhibit some dynamical and structural ordering. The structural plasticity of IDPs indicates that entropy-driven motions are crucial for their function. Many IDPs undergo function-related disorder-to-order transitions upon by their interaction with specific binding partners. Approaches that are based on both experimental and theoretical tools enable the biophysical characterization of IDPs. Molecular simulations provide insights into IDP structural ensembles and disorder-to-order transition mechanisms. However, such studies depend strongly on the chosen force field parameters and simulation techniques. In this chapter, we provide an overview of IDP characteristics, review all-atom force fields recently developed for IDPs, and present molecular dynamics-based simulation methods that allow IDP ensemble generation as well as the characterization of disorder-to-order transitions. In particular, we introduce metadynamics, replica exchange molecular dynamics simulations, and also kinetic models resulting from Markov State modeling, and provide various examples for the successful application of these simulation methods to IDPs.
    MeSH term(s) Humans ; Intrinsically Disordered Proteins ; Molecular Dynamics Simulation ; Protein Conformation
    Chemical Substances Intrinsically Disordered Proteins
    Language English
    Publishing date 2021-07-29
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2471995-X
    ISSN 1878-0814 ; 0079-6603 ; 1877-1173
    ISSN (online) 1878-0814
    ISSN 0079-6603 ; 1877-1173
    DOI 10.1016/bs.pmbts.2021.06.003
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    Uc I Zs 357: Show issues Location:
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  8. Article ; Online: Molecular Dynamics Simulations of Protein Aggregation: Protocols for Simulation Setup and Analysis with Markov State Models and Transition Networks.

    Samantray, Suman / Schumann, Wibke / Illig, Alexander-Maurice / Carballo-Pacheco, Martin / Paul, Arghadwip / Barz, Bogdan / Strodel, Birgit

    Methods in molecular biology (Clifton, N.J.)

    2022  Volume 2340, Page(s) 235–279

    Abstract: Protein disorder and aggregation play significant roles in the pathogenesis of numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. The end products of the aggregation process in these diseases are highly structured amyloid ... ...

    Abstract Protein disorder and aggregation play significant roles in the pathogenesis of numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. The end products of the aggregation process in these diseases are highly structured amyloid fibrils. Though in most cases, small, soluble oligomers formed during amyloid aggregation are the toxic species. A full understanding of the physicochemical forces that drive protein aggregation is thus required if one aims for the rational design of drugs targeting the formation of amyloid oligomers. Among a multitude of biophysical and biochemical techniques that are employed for studying protein aggregation, molecular dynamics (MD) simulations at the atomic level provide the highest temporal and spatial resolution of this process, capturing key steps during the formation of amyloid oligomers. Here we provide a step-by-step guide for setting up, running, and analyzing MD simulations of aggregating peptides using GROMACS. For the analysis, we provide the scripts that were developed in our lab, which allow to determine the oligomer size and inter-peptide contacts that drive the aggregation process. Moreover, we explain and provide the tools to derive Markov state models and transition networks from MD data of peptide aggregation.
    MeSH term(s) Amyloid ; Amyloid beta-Peptides ; Humans ; Molecular Dynamics Simulation ; Neurodegenerative Diseases ; Protein Aggregates
    Chemical Substances Amyloid ; Amyloid beta-Peptides ; Protein Aggregates
    Language English
    Publishing date 2022-02-15
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-1546-1_12
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  9. Book ; Online ; Thesis: Essays on the interplay between glycosaminoglycans and amyloid-β peptides

    Samantray, Suman [Verfasser] / Lüchow, Arne [Akademischer Betreuer] / Strodel, Birgit [Akademischer Betreuer]

    2021  

    Author's details Suman Samantray ; Arne Lüchow, Birgit Strodel
    Keywords Biowissenschaften, Biologie ; Life Science, Biology
    Subject code sg570
    Language English
    Publisher Universitätsbibliothek der RWTH Aachen
    Publishing place Aachen
    Document type Book ; Online ; Thesis
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  10. Article ; Online: β-Turn mimetic synthetic peptides as amyloid-β aggregation inhibitors.

    Deike, Stefanie / Rothemund, Sven / Voigt, Bruno / Samantray, Suman / Strodel, Birgit / Binder, Wolfgang H

    Bioorganic chemistry

    2020  Volume 101, Page(s) 104012

    Abstract: Aggregation of amyloid peptides results in severe neurodegenerative diseases. While the fibril structures of ... ...

    Abstract Aggregation of amyloid peptides results in severe neurodegenerative diseases. While the fibril structures of Aβ
    MeSH term(s) Amino Acids/chemistry ; Amyloid beta-Peptides/antagonists & inhibitors ; Amyloid beta-Peptides/chemistry ; Biopolymers/chemistry ; Cell Line ; Cell Survival/drug effects ; Humans ; Molecular Dynamics Simulation ; Molecular Mimicry
    Chemical Substances Amino Acids ; Amyloid beta-Peptides ; Biopolymers
    Language English
    Publishing date 2020-06-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120080-x
    ISSN 1090-2120 ; 0045-2068
    ISSN (online) 1090-2120
    ISSN 0045-2068
    DOI 10.1016/j.bioorg.2020.104012
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    Zs.A 4207: Show issues Location:
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