Molecular dynamics simulations of an α-synuclein NAC domain fragment with a ff14IDPSFF IDP-specific force field suggest β-sheet intermediate states of fibrillation

Privat, Cristian; Madurga, Sergio; Mas, Francesc; Rubio-Martínez, Jaime

doi:10.1039/d2cp02042d

Cited by 1 publication

(4 citation statements)

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“… 160 While ff14SB preserved the α-helices in α-synuclein, ff14IDPSFF predicted increased disorder and indicated the formation of β-sheet structures. 160 Other strategies involve adding CMAP corrections to both side chain and backbone dihedrals (RSFF2C 161 ) and adding corrections based on the chemical environment around a given aa (ESFF1 162 ). Rahman et al 142 found that the IDP-specific force fields obtain more reasonable results for pure IDPs.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

“…ff03CMAP is an example of another ff that works for both folded (in combination with TIP4P-Ew , ) and disordered proteins (in combination with TIP4P-D). Some other ff s like ff14IDPSFF , (modified from AMBER ff14SB) and CHARMM36IDPSFF , (modified from CHARMM36m) are CMAP-based and IDP-specific. The latter has been shown to reproduce the experimental conformational ensemble of multiple disordered proteins .…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

“…The latter has been shown to reproduce the experimental conformational ensemble of multiple disordered proteins . In a recent study, Privat et al found that ff14IDPSFF could accurately predict experimental chemical shifts for α-synuclein . While ff14SB preserved the α-helices in α-synuclein, ff14IDPSFF predicted increased disorder and indicated the formation of β-sheet structures .…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

“…In a recent study, Privat et al found that ff14IDPSFF could accurately predict experimental chemical shifts for α-synuclein . While ff14SB preserved the α-helices in α-synuclein, ff14IDPSFF predicted increased disorder and indicated the formation of β-sheet structures . Other strategies involve adding CMAP corrections to both side chain and backbone dihedrals (RSFF2C) and adding corrections based on the chemical environment around a given aa (ESFF1).…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

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Fuzzy Drug Targets: Disordered Proteins in the Drug-Discovery Realm

et al. 2023

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Intrinsically disordered proteins (IDPs) and regions (IDRs) form a large part of the eukaryotic proteome. Contrary to the structure−function paradigm, the disordered proteins perform a myriad of functions in vivo. Consequently, they are involved in various disease pathways and are plausible drug targets. Unlike folded proteins, that have a defined structure and well carved out drug-binding pockets that can guide lead molecule selection, the disordered proteins require alternative drug-development methodologies that are based on an acceptable picture of their conformational ensemble. In this review, we discuss various experimental and computational techniques that contribute toward understanding IDP "structure" and describe representative pursuances toward IDP-targeting drug development. We also discuss ideas on developing rational drug design protocols targeting IDPs.

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