Matthes, Dirk

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Frieg, Benedikt"],["dc.contributor.author","Antonschmidt, Leif"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Geraets, James A."],["dc.contributor.author","Najbauer, Eszter E."],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","de Groot, Bert L."],["dc.contributor.author","Andreas, Loren B."],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Griesinger, Christian"],["dc.contributor.author","Schröder, Gunnar F."],["dc.date.accessioned","2022-12-01T08:30:50Z"],["dc.date.available","2022-12-01T08:30:50Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract\n α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson’s disease, in which α-synuclein fibrils are a characteristic hallmark of neuronal inclusions called Lewy bodies. Studies on the composition of Lewy bodies extracted postmortem from brain tissue of Parkinson’s patients revealed that lipids and membranous organelles are also a significant component. Interactions between α-synuclein and lipids have been previously identified as relevant for Parkinson’s disease pathology, however molecular insights into their interactions have remained elusive. Here we present cryo-electron microscopy structures of six α-synuclein fibrils in complex with lipids, revealing specific lipid-fibril interactions. We observe that phospholipids promote an alternative protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities of the fibrils. Together with our previous studies, these structures also indicate a mechanism for fibril-induced lipid extraction, which is likely to be involved in the development of α-synucleinopathies. Specifically, one potential mechanism for the cellular toxicity is the disruption of intracellular vesicles mediated by fibrils and oligomers, and therefore the modulation of these interactions may provide a promising strategy for future therapeutic interventions."],["dc.identifier.doi","10.1038/s41467-022-34552-7"],["dc.identifier.pii","34552"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/117993"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-621"],["dc.relation.eissn","2041-1723"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","The 3D structure of lipidic fibrils of α-synuclein"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","Gapsys, Vytautas"],["dc.contributor.author","Brennecke, Julian T."],["dc.contributor.author","de Groot, Bert L."],["dc.date.accessioned","2021-03-05T08:58:33Z"],["dc.date.available","2021-03-05T08:58:33Z"],["dc.date.issued","2016"],["dc.identifier.doi","10.1038/srep33156"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/80179"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-393"],["dc.relation.eissn","2045-2322"],["dc.title","An Atomistic View of Amyloidogenic Self-assembly: Structure and Dynamics of Heterogeneous Conformational States in the Pre-nucleation Phase"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","650a"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Biophysical Journal"],["dc.bibliographiccitation.volume","98"],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","de Groot, Bert L."],["dc.date.accessioned","2021-03-05T08:57:50Z"],["dc.date.available","2021-03-05T08:57:50Z"],["dc.date.issued","2010"],["dc.identifier.doi","10.1016/j.bpj.2009.12.3561"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/79901"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-393"],["dc.relation.issn","0006-3495"],["dc.title","The Spontaneous Aggregation of Steric Zipper Peptides Studied by Molecular Dynamics Simulations"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","402a"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Biophysical Journal"],["dc.bibliographiccitation.volume","110"],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","Gapsys, Vytautas"],["dc.contributor.author","Brennecke, Julian T."],["dc.contributor.author","de Groot, Bert L."],["dc.date.accessioned","2021-03-05T08:58:00Z"],["dc.date.available","2021-03-05T08:58:00Z"],["dc.date.issued","2016"],["dc.identifier.doi","10.1016/j.bpj.2015.11.2170"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/79964"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-393"],["dc.relation.issn","0006-3495"],["dc.title","Global and Local Conformational Heterogeniety Governs the Pre-Nucleation Phase in Amyloidogenic Self-Assembly"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","e19129"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","PLoS One"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","Gapsys, Vytautas"],["dc.contributor.author","Daebel, Venita"],["dc.contributor.author","de Groot, Bert L."],["dc.contributor.editor","Pastore, Annalisa"],["dc.date.accessioned","2021-03-05T08:59:12Z"],["dc.date.available","2021-03-05T08:59:12Z"],["dc.date.issued","2011"],["dc.identifier.doi","10.1371/journal.pone.0019129"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/80396"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-393"],["dc.relation.eissn","1932-6203"],["dc.title","Mapping the Conformational Dynamics and Pathways of Spontaneous Steric Zipper Peptide Oligomerization"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2791"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","ASC Chemical Neuroscience"],["dc.bibliographiccitation.lastpage","2808"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","Gapsys, Vytautas"],["dc.contributor.author","Griesinger, Christian"],["dc.contributor.author","de Groot, Bert L."],["dc.date.accessioned","2018-01-17T11:26:28Z"],["dc.date.available","2018-01-17T11:26:28Z"],["dc.date.issued","2017"],["dc.description.abstract","The diphenyl-pyrazole compound anle138b is a known inhibitor of oligomeric aggregate formation in vitro and in vivo. Therefore, anle138b is considered a promising drug candidate to beneficially interfere with neurodegenerative processes causing devastating pathologies in humans. The atomistic details of the aggregation inhibition mechanism, however, are to date unknown since the ensemble of small nonfibrillar aggregates is structurally heterogeneous and inaccessible to direct structural characterization. Here, we set out to elucidate anle138b's mode of action using all-atom molecular dynamics simulations on the multi-microsecond time scale. By comparing simulations of dimeric to tetrameric aggregates from fragments of four amyloidogenic proteins (Aβ, hTau40, hIAPP, and Sup35N) in the presence and absence of anle138b, we show that the compound reduces the overall number of intermolecular hydrogen bonds, disfavors the sampling of the aggregated state, and remodels the conformational distributions within the small oligomeric peptide aggregates. Most notably, anle138b preferentially interacts with the disordered structure ensemble via its pyrazole moiety, thereby effectively blocking interpeptide main chain interactions and impeding the spontaneous formation of ordered β-sheet structures, in particular those with out-of-register antiparallel β-strands. The structurally very similar compound anle234b was previously identified as inactive by in vitro experiments. Here, we show that anle234b has no significant effect on the aggregation process in terms of reducing the β-structure content. Moreover, we demonstrate that the hydrogen bonding capabilities are autoinhibited due to steric effects imposed by the molecular geometry of anle234b and thereby indirectly confirm the proposed inhibitory mechanism of anle138b. We anticipate that the prominent binding of anle138b to partially disordered and dynamical aggregate structures is a generic basis for anle138b's ability to suppress toxic oligomer formation in a wide range of amyloidogenic peptides and proteins."],["dc.identifier.doi","10.1021/acschemneuro.7b00325"],["dc.identifier.pmid","28906103"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/11674"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1948-7193"],["dc.title","Resolving the Atomistic Modes of Anle138b Inhibitory Action on Peptide Oligomer Formation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","599"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Biophysical Journal"],["dc.bibliographiccitation.lastpage","608"],["dc.bibliographiccitation.volume","97"],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","de Groot, Bert L."],["dc.date.accessioned","2021-03-05T09:05:26Z"],["dc.date.available","2021-03-05T09:05:26Z"],["dc.date.issued","2009"],["dc.identifier.doi","10.1016/j.bpj.2009.04.061"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/80474"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-393"],["dc.relation.issn","0006-3495"],["dc.title","Secondary Structure Propensities in Peptide Folding Simulations: A Systematic Comparison of Molecular Mechanics Interaction Schemes"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Antonschmidt, Leif"],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","Dervişoğlu, Rıza"],["dc.contributor.author","Frieg, Benedikt"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Leonov, Andrei"],["dc.contributor.author","Nimerovsky, Evgeny"],["dc.contributor.author","Sant, Vrinda"],["dc.contributor.author","Ryazanov, Sergey"],["dc.contributor.author","Giese, Armin"],["dc.contributor.author","Andreas, Loren B."],["dc.date.accessioned","2022-10-04T10:21:08Z"],["dc.date.available","2022-10-04T10:21:08Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract\n Aggregation of amyloidogenic proteins is a characteristic of multiple neurodegenerative diseases. Atomic resolution of small molecule binding to such pathological protein aggregates is of interest for the development of therapeutics and diagnostics. Here we investigate the interaction between α-synuclein fibrils and anle138b, a clinical drug candidate for disease modifying therapy in neurodegeneration and a promising scaffold for positron emission tomography tracer design. We used nuclear magnetic resonance spectroscopy and the cryogenic electron microscopy structure of α-synuclein fibrils grown in the presence of lipids to locate anle138b within a cavity formed between two β-strands. We explored and quantified multiple binding modes of the compound in detail using molecular dynamics simulations. Our results reveal stable polar interactions between anle138b and backbone moieties inside the tubular cavity of the fibrils. Such cavities are common in other fibril structures as well."],["dc.identifier.doi","10.1038/s41467-022-32797-w"],["dc.identifier.pii","32797"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/114336"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-600"],["dc.relation.eissn","2041-1723"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1816"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","ChemBioChem"],["dc.bibliographiccitation.lastpage","1822"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Haas, Jürgen"],["dc.contributor.author","Vöhringer-Martinez, Esteban"],["dc.contributor.author","Bögehold, Andreas"],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","Hensen, Ulf"],["dc.contributor.author","Pelah, Avishay"],["dc.contributor.author","Abel, Bernd"],["dc.contributor.author","Grubmüller, Helmut"],["dc.date.accessioned","2021-03-05T08:58:01Z"],["dc.date.available","2021-03-05T08:58:01Z"],["dc.date.issued","2009"],["dc.identifier.doi","10.1002/cbic.200900266"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/79971"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-393"],["dc.relation.issn","1439-4227"],["dc.title","Primary Steps of pH-Dependent Insulin Aggregation Kinetics are Governed by Conformational Flexibility"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1742"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","ChemBioChem"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Haas, Jürgen"],["dc.contributor.author","Vöhringer-Martinez, Esteban"],["dc.contributor.author","Bögehold, Andreas"],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","Hensen, Ulf"],["dc.contributor.author","Pelah, Avishay"],["dc.contributor.author","Abel, Bernd"],["dc.contributor.author","Grubmüller, Helmut"],["dc.date.accessioned","2017-09-07T11:52:30Z"],["dc.date.available","2017-09-07T11:52:30Z"],["dc.date.issued","2009"],["dc.description.abstract","Insulin aggregation critically depends on pH. The underlying energetic and structural determinants are, however, unknown. Here, we measure the kinetics of the primary aggregation steps of the insulin monomer in vitro and relate it to its conformational flexibility. To assess these primary steps the monomer concentration was monitored by mass spectrometry at various pH values and aggregation products were imaged by atomic force microscopy. Lowering the pH from 3 to 1.6 markedly accelerated the observed aggregation kinetics. The influence of pH on the monomer structure and dynamics in solution was studied by molecular dynamics simulations, with the protonation states of the titrable groups obtained from electrostatic calculations. Reduced flexibility was observed for low pH values, mainly in the C terminus and in the helix of the B chain; these corresponded to an estimated entropy loss of 150 J mol−1 K−1. The striking correlation between entropy loss and pH value is consistent with the observed kinetic traces. In analogy to the well-known Φ value analysis, this result allows the extraction of structural information about the rate determining transition state of the primary aggregation steps. In particular, we suggest that the residues in the helix of the B chain are involved in this transition state."],["dc.identifier.doi","10.1002/cbic.200990042"],["dc.identifier.gro","3144942"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2621"],["dc.language.iso","en"],["dc.notes.intern","Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","1439-4227"],["dc.title","Inside Cover: Primary Steps of pH‐Dependent Insulin Aggregation Kinetics are Governed by Conformational Flexibility (ChemBioChem 11/2009)"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]