TY  - JOUR
AU  - Robustelli, Paul
AU  - Ibanez de Opakua, Alain
AU  - Campbell-Bezat, Cecily
AU  - Giordanetto, Fabrizio
AU  - Becker, Stefan
AU  - Zweckstetter, Markus
AU  - Pan, Albert C
AU  - Shaw, David E
TI  - Molecular Basis of Small-Molecule Binding to α-Synuclein.
JO  - Journal of the American Chemical Society
VL  - 144
IS  - 6
SN  - 1520-5126
CY  - Washington, DC
PB  - American Chemical Society
M1  - DZNE-2022-00161
SP  - 2501 - 2510
PY  - 2022
N1  - (CC BY-NC-ND)
AB  - 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.
KW  - 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: analogs & derivatives
KW  - 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: chemistry
KW  - 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: metabolism
KW  - Amino Acid Sequence
KW  - Hydrogen Bonding
KW  - Intrinsically Disordered Proteins: chemistry
KW  - Intrinsically Disordered Proteins: metabolism
KW  - Ligands
KW  - Molecular Conformation
KW  - Molecular Dynamics Simulation
KW  - Protein Binding
KW  - Small Molecule Libraries: chemistry
KW  - Small Molecule Libraries: metabolism
KW  - alpha-Synuclein: metabolism
KW  - Intrinsically Disordered Proteins (NLM Chemicals)
KW  - Ligands (NLM Chemicals)
KW  - Small Molecule Libraries (NLM Chemicals)
KW  - alpha-Synuclein (NLM Chemicals)
KW  - 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (NLM Chemicals)
KW  - fasudil (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:35130691
C2  - pmc:PMC8855421
DO  - DOI:10.1021/jacs.1c07591
UR  - https://pub.dzne.de/record/163399
ER  -