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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00894-022-05244-2.