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  1. Article ; Online: Comparative molecular dynamics simulations of pathogenic and non-pathogenic huntingtin protein monomers and dimers

    Mohammed Khaled / Birgit Strodel / Abdallah Sayyed-Ahmad

    Frontiers in Molecular Biosciences, Vol

    2023  Volume 10

    Abstract: Polyglutamine expansion at the N-terminus of the huntingtin protein exon 1 (Htt-ex1) is closely associated with a number of neurodegenerative diseases, which result from the aggregation of the increased polyQ repeat. However, the underlying structures ... ...

    Abstract Polyglutamine expansion at the N-terminus of the huntingtin protein exon 1 (Htt-ex1) is closely associated with a number of neurodegenerative diseases, which result from the aggregation of the increased polyQ repeat. However, the underlying structures and aggregation mechanism are still poorly understood. We performed microsecond-long all-atom molecular dynamics simulations to study the folding and dimerization of Htt-ex1 (about 100 residues) with non-pathogenic and pathogenic polyQ lengths, and uncovered substantial differences. The non-pathogenic monomer adopts a long α-helix that includes most of the polyQ residues, which forms the interaction interface for dimerization, and a PPII-turn-PPII motif in the proline-rich region. In the pathogenic monomer, the polyQ region is disordered, leading to compact structures with many intra-protein interactions and the formation of short β-sheets. Dimerization can proceed via different modes, where those involving the N-terminal headpiece bury more hydrophobic residues and are thus more stable. Moreover, in the pathogenic Htt-ex1 dimers the proline-rich region interacts with the polyQ region, which slows the formation of β-sheets.
    Keywords polyglutamine ; huntingtin ; molecular dynamics ; oligomer ; aggregation ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2023-04-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: The Influences of Sulphation, Salt Type, and Salt Concentration on the Structural Heterogeneity of Glycosaminoglycans

    Suman Samantray / Olujide O. Olubiyi / Birgit Strodel

    International Journal of Molecular Sciences, Vol 22, Iss 11529, p

    2021  Volume 11529

    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.
    Keywords glycosaminoglycans ; sulphation ; GAG–cation interactions ; conformational flexibility ; molecular dynamics simulations ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 540
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Structural Dissection of the First Events Following Membrane Binding of the Islet Amyloid Polypeptide

    Lucie Khemtemourian / Hebah Fatafta / Benoit Davion / Sophie Lecomte / Sabine Castano / Birgit Strodel

    Frontiers in Molecular Biosciences, Vol

    2022  Volume 9

    Abstract: The islet amyloid polypeptide (IAPP) is the main constituent of the amyloid fibrils found in the pancreas of type 2 diabetes patients. The aggregation of IAPP is known to cause cell death, where the cell membrane plays a dual role: being a catalyst of ... ...

    Abstract The islet amyloid polypeptide (IAPP) is the main constituent of the amyloid fibrils found in the pancreas of type 2 diabetes patients. The aggregation of IAPP is known to cause cell death, where the cell membrane plays a dual role: being a catalyst of IAPP aggregation and being the target of IAPP toxicity. Using ATR-FTIR spectroscopy, transmission electron microscopy, and molecular dynamics simulations we investigate the very first molecular steps following IAPP binding to a lipid membrane. In particular, we assess the combined effects of the charge state of amino-acid residue 18 and the IAPP-membrane interactions on the structures of monomeric and aggregated IAPP. Distinct IAPP-membrane interaction modes for the various IAPP variants are revealed. Membrane binding causes IAPP to fold into an amphipathic α-helix, which in the case of H18K-, and H18R-IAPP readily moves beyond the headgroup region. For all IAPP variants but H18E-IAPP, the membrane-bound helix is an intermediate on the way to amyloid aggregation, while H18E-IAPP remains in a stable helical conformation. The fibrillar aggregates of wild-type IAPP and H18K-IAPP are dominated by an antiparallel β-sheet conformation, while H18R- and H18A-IAPP exhibit both antiparallel and parallel β-sheets as well as amorphous aggregates. Our results emphasize the decisive role of residue 18 for the structure and membrane interaction of IAPP. This residue is thus a good therapeutic target for destabilizing membrane-bound IAPP fibrils to inhibit their toxic actions.
    Keywords islet amyloid polypeptide ; type 2 diabetes mellitus ; amylin ; amyloid aggregation ; peptide-membrane interactions ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Large-scale, dynamin-like motions of the human guanylate binding protein 1 revealed by multi-resolution simulations.

    Bogdan Barz / Jennifer Loschwitz / Birgit Strodel

    PLoS Computational Biology, Vol 15, Iss 10, p e

    2019  Volume 1007193

    Abstract: Guanylate binding proteins (GBPs) belong to the dynamin-related superfamily and exhibit various functions in the fight against infections. The functions of the human guanylate binding protein 1 (hGBP1) are tightly coupled to GTP hydrolysis and ... ...

    Abstract Guanylate binding proteins (GBPs) belong to the dynamin-related superfamily and exhibit various functions in the fight against infections. The functions of the human guanylate binding protein 1 (hGBP1) are tightly coupled to GTP hydrolysis and dimerization. Despite known crystal structures of the hGBP1 monomer and GTPase domain dimer, little is known about the dynamics of hGBP1. To gain a mechanistic understanding of hGBP1, we performed sub-millisecond multi-resolution molecular dynamics simulations of both the hGBP1 monomer and dimer. We found that hGBP1 is a highly flexible protein that undergoes a hinge motion similar to the movements observed for other dynamin-like proteins. Another large-scale motion was observed for the C-terminal helix α13, providing a molecular view for the α13-α13 distances previously reported for the hGBP1 dimer. Most of the loops of the GTPase domain were found to be flexible, revealing why GTP binding is needed for hGBP1 dimerization to occur.
    Keywords Biology (General) ; QH301-705.5
    Subject code 500
    Language English
    Publishing date 2019-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Topology and parameter data of thirteen non-natural amino acids for molecular simulations with CHARMM22

    Olujide O. Olubiyi / Birgit Strodel

    Data in Brief, Vol 9, Iss C, Pp 642-

    2016  Volume 647

    Abstract: In this article we provide a data package containing the topology files and parameters compatible with the CHARMM22 force field for thirteen non-natural amino acids. The force field parameters were derived based on quantum mechanical (QM) calculations ... ...

    Abstract In this article we provide a data package containing the topology files and parameters compatible with the CHARMM22 force field for thirteen non-natural amino acids. The force field parameters were derived based on quantum mechanical (QM) calculations involving geometry optimization and potential energy surface scanning at the HF 6-31G(d) and HF 6-311G(d,p) levels of theory. The resulting energy data points were fitted to mathematical functions representing each component of the CHARMM22 force field. Further fine-tuning of the parameters utilized molecular mechanics energies, which were iteratively calculated and compared to the corresponding QM values until the latter were satisfactorily reproduced. The final force field data were validated with molecular dynamics simulations in explicit solvent conditions.
    Keywords CHARMM ; Force field parameterization ; Quantum mechanics ; Molecular dynamics ; Potential energy surface ; Geometry optimization ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Science (General) ; Q1-390
    Subject code 541
    Language English
    Publishing date 2016-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Dataset of AMBER force field parameters of drugs, natural products and steroids for simulations using GROMACS

    Jennifer Loschwitz / Anna Jäckering / Monika Keutmann / Maryam Olagunju / Olujide O. Olubiyi / Birgit Strodel

    Data in Brief, Vol 35, Iss , Pp 106948- (2021)

    2021  

    Abstract: We provide general AMBER force field (GAFF) parameters for 160 organic molecules including drugs, natural products, and steroids, which can be employed without further processing in molecular dynamics (MD) simulations using GROMACS. We determined these ... ...

    Abstract We provide general AMBER force field (GAFF) parameters for 160 organic molecules including drugs, natural products, and steroids, which can be employed without further processing in molecular dynamics (MD) simulations using GROMACS. We determined these parameters based on quantum mechanical (QM) calculations involving geometry optimization at the HF6-31G* level of theory. For each molecule we provide a coordinate file of the three-dimensional molecular structure, the topology and the parameter file. The applicability of these parameters was demonstrated by MD simulations of these molecules bound to the active site of the main protease of the coronavirus SARS-CoV-2, 3CLpro, which is a main player during viral replication causing COVID-19.
    Keywords force field parameterization ; AMBER force field ; MD simulations ; GROMACS ; Quantum mechanics ; drugs ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Science (General) ; Q1-390
    Subject code 612
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2

    Olujide O. Olubiyi / Maryam Olagunju / Monika Keutmann / Jennifer Loschwitz / Birgit Strodel

    Molecules, Vol 25, Iss 3193, p

    2020  Volume 3193

    Abstract: We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CL pro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over ... ...

    Abstract We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CL pro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CL pro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CL pro enzyme of the closely related SARS-CoV virus. The top-ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CL pro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CL pro . Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CL pro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.
    Keywords COVID-19 ; docking ; drug repurposing ; natural products ; in silico drug design ; viral replication inhibition ; Organic chemistry ; QD241-441 ; covid19
    Subject code 540
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article: Pathways of Amyloid-β Aggregation Depend on Oligomer Shape

    Barz, Bogdan / Birgit Strodel / Qinghua Liao

    Journal of the American Chemical Society. 2018 Jan. 10, v. 140, no. 1

    2018  

    Abstract: One of the main research topics related to Alzheimer’s disease is the aggregation of the amyloid-β peptide, which was shown to follow different pathways for the two major alloforms of the peptide, Aβ40 and the more toxic Aβ42. Experimental studies ... ...

    Abstract One of the main research topics related to Alzheimer’s disease is the aggregation of the amyloid-β peptide, which was shown to follow different pathways for the two major alloforms of the peptide, Aβ40 and the more toxic Aβ42. Experimental studies emphasized that oligomers of specific sizes appear in the early aggregation process in different quantities and might be the key toxic agents for each of the two alloforms. We use transition networks derived from all-atom molecular dynamics simulations to show that the oligomers leading to the type of oligomer distributions observed in experiments originate from compact conformations. Extended oligomers, on the other hand, contribute more to the production of larger aggregates thus driving the aggregation process. We further demonstrate that differences in the aggregation pathways of the two Aβ alloforms occur as early as during the dimer stage. The higher solvent-exposure of hydrophobic residues in Aβ42 oligomers contributes to the different aggregation pathways of both alloforms and also to the increased cytotoxicity of Aβ42.
    Keywords Alzheimer disease ; cytotoxicity ; hydrophobicity ; molecular dynamics ; simulation models
    Language English
    Dates of publication 2018-0110
    Size p. 319-327.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021/jacs.7b10343
    Database NAL-Catalogue (AGRICOLA)

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  9. Article ; Online: Stability of transmembrane amyloid β-peptide and membrane integrity tested by molecular modeling of site-specific Aβ42 mutations.

    Chetan Poojari / Birgit Strodel

    PLoS ONE, Vol 8, Iss 11, p e

    2013  Volume 78399

    Abstract: Interactions of the amyloid β-protein (Aβ) with neuronal cell membranes, leading to the disruption of membrane integrity, are considered to play a key role in the development of Alzheimer's disease. Natural mutations in Aβ42, such as the Arctic mutation ( ...

    Abstract Interactions of the amyloid β-protein (Aβ) with neuronal cell membranes, leading to the disruption of membrane integrity, are considered to play a key role in the development of Alzheimer's disease. Natural mutations in Aβ42, such as the Arctic mutation (E22G) have been shown to increase Aβ42 aggregation and neurotoxicity, leading to the early-onset of Alzheimer's disease. A correlation between the propensity of Aβ42 to form protofibrils and its effect on neuronal dysfunction and degeneration has been established. Using rational mutagenesis of the Aβ42 peptide it was further revealed that the aggregation of different Aβ42 mutants in lipid membranes results in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also have a variable ability to disrupt bilayer integrity. To further test the connection between Aβ42 mutation and peptide-membrane interactions, we perform molecular dynamics simulations of membrane-inserted Aβ42 variants (wild-type and E22G, D23G, E22G/D23G, K16M/K28M and K16M/E22G/D23G/K28M mutants) as β-sheet monomers and tetramers. The effects of charged residues on transmembrane Aβ42 stability and membrane integrity are analyzed at atomistic level. We observe an increased stability for the E22G Aβ42 peptide and a decreased stability for D23G compared to wild-type Aβ42, while D23G has the largest membrane-disruptive effect. These results support the experimental observation that the altered toxicity arising from mutations in Aβ is not only a result of the altered aggregation propensity, but also originates from modified Aβ interactions with neuronal membranes.
    Keywords Medicine ; R ; Science ; Q
    Subject code 612
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Interference with Amyloid-β Nucleation by Transient Ligand Interaction

    Tao Zhang / Jennifer Loschwitz / Birgit Strodel / Luitgard Nagel-Steger / Dieter Willbold

    Molecules, Vol 24, Iss 11, p

    2019  Volume 2129

    Abstract: Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. ... ...

    Abstract Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting drug candidates that combine high binding specificity with high metabolic stability. Here we characterized the interaction between the 12-residue all-D-peptide D3 and Aβ42 monomers, and how the interaction influences Aβ42 aggregation. We demonstrate for the first time that D3 binds to Aβ42 monomers with submicromolar affinities. These two highly unstructured molecules are able to form complexes with 1:1 and other stoichiometries. Further, D3 at substoichiometric concentrations effectively slows down the β-sheet formation and Aβ42 fibrillation by modulating the nucleation process. The study provides new insights into the molecular mechanism of how D3 affects Aβ assemblies and contributes to our knowledge on the interaction between two IDPs.
    Keywords amyloid-β peptides ; aggregation ; complex formation ; D-enantiomeric peptide ; intrinsically disordered protein ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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