163399 20240320115517.0 10.1021/jacs.1c07591 doi pmid:35130691 pmid pmc:PMC8855421 pmc 0002-7863 ISSN 1520-5126 ISSN 1943-2984 ISSN altmetric:122591676 altmetric DZNE-2022-00161 English 540 Robustelli, Paul 0 Molecular Basis of Small-Molecule Binding to α-Synuclein. Washington, DC 2022 American Chemical Society article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1655210655_923 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote (CC BY-NC-ND) Intrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-time-scale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson's disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de Intrinsically Disordered Proteins NLM Chemicals Ligands NLM Chemicals Small Molecule Libraries NLM Chemicals alpha-Synuclein NLM Chemicals 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine 84477-87-2 NLM Chemicals fasudil Q0CH43PGXS NLM Chemicals 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: analogs & derivatives MeSH 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: chemistry MeSH 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: metabolism MeSH Amino Acid Sequence MeSH Hydrogen Bonding MeSH Intrinsically Disordered Proteins: chemistry MeSH Intrinsically Disordered Proteins: metabolism MeSH Ligands MeSH Molecular Conformation MeSH Molecular Dynamics Simulation MeSH Protein Binding MeSH Small Molecule Libraries: chemistry MeSH Small Molecule Libraries: metabolism MeSH alpha-Synuclein: metabolism MeSH Ibanez de Opakua, Alain P:(DE-2719)2812657 1 dzne Campbell-Bezat, Cecily 2 Giordanetto, Fabrizio 0000-0001-9876-9552 3 Becker, Stefan 4 Zweckstetter, Markus P:(DE-2719)2810591 5 dzne Pan, Albert C 6 Shaw, David E 0000-0001-8265-5761 7 10.1021/jacs.1c07591 Vol. 144, no. 6, p. 2501 - 2510 PERI:(DE-600)1472210-0 6 2501 - 2510 Journal of the American Chemical Society 144 2022 1520-5126 OpenAccess http://pub.dzne.de/record/163399/files/DZNE-2022-00161.pdf OpenAccess pdfa http://pub.dzne.de/record/163399/files/DZNE-2022-00161.pdf?subformat=pdfa oai:pub.dzne.de:163399 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 1 P:(DE-2719)2812657 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-2719)2810591 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 2022 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2022-11-09 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2022-11-09 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2022-11-09 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2021-01-30 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2022-11-09 Creative Commons Attribution-NonCommercial-NoDerivs CC BY-NC-ND 4.0 LIC:(DE-HGF)CCBYNCND4 HGFVOC IF >= 15 StatID:(DE-HGF)9915 StatID J AM CHEM SOC : 2021 2022-11-09 DBCoverage StatID:(DE-HGF)1200 StatID Chemical Reactions 2021-01-30 DBCoverage StatID:(DE-HGF)1150 StatID Current Contents - Physical, Chemical and Earth Sciences 2022-11-09 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2021-01-30 DBCoverage StatID:(DE-HGF)1210 StatID Index Chemicus 2021-01-30 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2022-11-09 OpenAccess StatID:(DE-HGF)0510 StatID DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2022-11-09 Peer Review StatID:(DE-HGF)0030 StatID ASC 2022-11-09 JCR StatID:(DE-HGF)0100 StatID J AM CHEM SOC : 2021 2022-11-09 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2021-01-30 Nationallizenz StatID:(DE-HGF)0420 StatID 2022-11-09 ger DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2022-11-09 I:(DE-2719)1410001 AG Zweckstetter Structural Biology in Dementia 0 journal VDB UNRESTRICTED I:(DE-2719)1410001 FullTexts