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An insight of early PrP‐E200K aggregation by combined molecular dynamics/fragment molecular orbital approaches
Author(s) -
Paciotti Roberto,
Storchi Loriano,
Marrone Alessandro
Publication year - 2019
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.25621
Subject(s) - dimer , molecular dynamics , protein aggregation , fragment molecular orbital , scrapie , chemistry , prion protein , residue (chemistry) , mutant , biophysics , nanotechnology , biology , computational chemistry , biochemistry , materials science , gene , molecule , molecular orbital , medicine , disease , organic chemistry , pathology
Unveiling the events leading to the formation of prion particles is a nowadays challenge in the field of neurochemistry. Pathogenic mutants of prion protein (PrP) are characterized by both an intrinsic tendency to aggregation and scrapie conversion propensity. However, the question about a possible correlation between these two events lasts still unanswered. Here, a multilayered computational workflow was employed to investigate structure, stability, and molecular interaction properties of a dimer of PrP C ‐E200K, a well‐known mutant of the PrP that represents a reduced model of early aggregates of this protein. Based on the combination of molecular dynamics and quantum mechanical approaches, this study provided for an in depth insight of PrP C ‐E200K dimer in terms of residue‐residue interactions. Assembly hypotheses for the early aggregation of PrP C ‐E200K are paved and compared with PrP Sc models reported in the literature to find a structural link between early and late (scrapie) aggregates of this protein.