Molecular Details of the Apolipoprotein E and the Amyloid Beta Peptide Interaction: Analysis of a Potential Binding Site Responsible for ApoE4 Misfolding

Abstract

The relationship between Apolipoprotein E (ApoE) and the aggregation processes of the amyloid β (Aβ) peptide has been shown to be crucial for Alzheimer's disease (AD). ApoE4 is considered as a contributing risk factor for AD. Although various mechanisms have been proposed to explain the physiological and pathological role of this relationship, the detailed molecular properties of ApoE4 interacting with Aβ peptide are unknown. In our studies, a peptide-protein docking approach has been used to investigate the process of Aβ interaction with the N-terminal domain of the human ApoE4 isoform. The use of molecular dynamics simulations (10 ns in water) has allowed studying the interaction mechanism between the protein and the peptide. Our results show that ApoE4 forms a partially unfolded intermediate (molten globule) stabilized by the interaction with Aβ. The initial SDS-induced α-helix used as Aβ peptide model, becomes unstructured due to the interaction with ApoE4. Peptide interaction with the different ApoE isoforms changed the pattern of the salt bridges network in ApoE4 compared to ApoE4 alone. By analysis and statistics of these electrostatic interaction patterns, we present a model for the salt bridge network in the ApoE4- Aβ complex, crucial for the understanding of the interaction mechanism and relevant for potential drug design and therapeutics.