Docking and Molecular Dynamics-Based Identification of Interaction between Various Beta-Amyloid Isoforms and RAGE Receptor

Beta-amyloid peptide (A beta) is a ligand associated with RAGE (Advanced glycosylation end product-specific receptor). A beta is translocated in complexes with RAGE from the blood to brain across the blood-brain barrier (BBB) by transcytosis. A beta and its isoforms are important factors in the Alzheimer's disease (AD) pathogenesis. However, interaction with RAGE was previously studied for A beta but not for its isoforms. The present study has been directed at identifying the key interaction interfaces between RAGE and A beta isoforms (A beta(40), A beta(42), phosphorylated and isomerized isoforms pS8-A beta(42), isoD7-A beta(42)). Two interfaces have been identified by docking: they are represented by an extended area at the junction of RAGE domains V and C1 and a smaller area linking C1 and C2 domains. Molecular dynamics (MD) simulations have shown that all A beta isoforms form stable and tightly bound complexes. This indicates that all A beta isoforms potentially can be transported through the cell as part of a complex with RAGE. Modeling of RAGE interaction interfaces with A beta indicates which chemical compounds can potentially be capable of blocking this interaction, and impair the associated pathogenic cascades. The ability of three RAGE inhibitors (RAP, FPS-ZM1 and RP-1) to disrupt the RAGE:A beta interaction has been probed by docking and subsequently the complexes' stability verified by MD. The RP-1 and A beta interaction areas coincide and therefore this inhibitor is very promising for the RAGE:A beta interaction inhibition.