Homodimeric complexes of the 90-231 human prion: a multilayered computational study based on FMO/GRID-DRY approach.
ATOMIF
E200K
FMO
GRID-DRY
Homodimeric complex
MEP
Prion
Protein–protein interaction
Journal
Journal of molecular modeling
ISSN: 0948-5023
Titre abrégé: J Mol Model
Pays: Germany
ID NLM: 9806569
Informations de publication
Date de publication:
02 Aug 2022
02 Aug 2022
Historique:
received:
01
06
2022
accepted:
25
07
2022
entrez:
2
8
2022
pubmed:
3
8
2022
medline:
5
8
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35918494
doi: 10.1007/s00894-022-05244-2
pii: 10.1007/s00894-022-05244-2
pmc: PMC9345805
doi:
Substances chimiques
Prions
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
241Informations de copyright
© 2022. The Author(s).
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