Molecular Dynamics Simulations of the Full-Length Prion Protein

Mamchur, Aleksandra A.; Panina, Irina; Yaroshevich, Igor A.; Kudryavtseva, Sofia S.

doi:10.1134/s1995080220080119

Cited by 2 publications

(3 citation statements)

References 37 publications

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“…The problem lies within its N-terminal domain, which is an intrinsically disordered region. Previously, we used a two-step approach consisting of de novo bioinformatic modelling and subsequent molecular dynamics ( Figure S11 ) to show that, although there is no stable conformation for the PrP N-domain, it forms a compact coil and contains characteristic contacts within [ 29 ]. In this work, we used the typical structure of the full length PrP to simulate its complex with GroEL.…”

Section: Resultsmentioning

confidence: 99%

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Structural and Computational Study of the GroEL–Prion Protein Complex

et al. 2021

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The molecular chaperone GroEL is designed to promote protein folding and prevent aggregation. However, the interaction between GroEL and the prion protein, PrPC, could lead to pathogenic transformation of the latter to the aggregation-prone PrPSc form. Here, the molecular basis of the interactions in the GroEL–PrP complex is studied with cryo-EM and molecular dynamics approaches. The obtained cryo-EM structure shows PrP to be bound to several subunits of GroEL at the level of their apical domains. According to MD simulations, the disordered N-domain of PrP forms much more intermolecular contacts with GroEL. Upon binding to the GroEL, the N-domain of PrP begins to form short helices, while the C-domain of PrP exhibits a tendency to unfold its α2-helix. In the absence of the nucleotides in the system, these processes are manifested at the hundred nanoseconds to microsecond timescale.

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Section: Resultsmentioning

confidence: 99%

“…Starting conformations of GroEL and PrP were chosen from a molecular dynamics simulation of two separated proteins, conducted by our group earlier [ 29 , 30 ]. The GroEL–PrP complex was assembled in two variants: GroEL–PrP(N) with the N-domain in the GroEL cavity and GroEL–PrP(C) with the C-domain in the GroEL cavity.…”

Section: Methodsmentioning

confidence: 99%

Structural and Computational Study of the GroEL–Prion Protein Complex

et al. 2021

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“…The multilayered procedure applied in this work can be improved for investigating unfolded protein by adopting specific FFs as CHARMM36m [ 62 ], a99SB-disp [ 63 ], and GROMOS 53a6 [ 64 ] that demonstrated to be suitable for conformational sampling of intrinsically disordered proteins as evidenced by recent works. For instance, the a99SB-disp FF, developed to capture the dynamics of both folded and disordered proteins, has been applied to study the V136R154Q171 mutant of the full-length PrP (residues 22–234) to predict the possible interdomain interactions involved in the misfolding process [ 65 ]. GROMOS 53a6 FF has been recently used (i) to address the early misfolding events of V210I-PrP mutant identifying possible aggregation-prone regions [ 66 ] and (ii) to study the aggregation process of 18 b-rich H2H3 fragments of the ovine PrP (H2H3-OvPrP Sc ) by performing atomistic molecular dynamics simulations in the sub-microsecond time-range [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Homodimeric complexes of the 90–231 human prion: a multilayered computational study based on FMO/GRID-DRY approach

2022

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The molecular interaction properties and aggregation capabilities disclosed by PrP-E200K, a pathogenic mutant of the human prion protein, were investigated in detail using multilayered computational approaches. In a previous work, we reported that the electrostatic complementarity between region1 (negative) and region3 (positive) has been assumed to lead to a head-to tail interaction between 120 and 231 PrP-E200K units and to initiation of the aggregation process. In this work, we extended the PrP-E200K structure by including the unstructured 90–120 segment which was found to assume different conformations. Plausible models of 90–231 PrP-E200K dimers were calculated and analyzed in depth to identify the nature of the involved protein–protein interactions. The unstructured 90–120 segment was found to extend the positively charged region3 involved in the association of PrP-E200K units which resulted to be driven by hydrophobic interactions. The combination of molecular dynamics, protein–protein docking, grid-based mapping, and fragment molecular orbital approaches allowed us to provide a plausible mechanism of the early state of 90–231 PrP-E200K aggregation, considered a preliminary step of amyloid conversion.

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Molecular Dynamics Simulations of the Full-Length Prion Protein

Cited by 2 publications

References 37 publications

Structural and Computational Study of the GroEL–Prion Protein Complex

Structural and Computational Study of the GroEL–Prion Protein Complex

Homodimeric complexes of the 90–231 human prion: a multilayered computational study based on FMO/GRID-DRY approach

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