Albumin Alters the Conformational Ensemble of Amyloid-β by Promiscuous Interactions: Implications for Amyloid Inhibition.

Abstract

Human serum albumin (HSA) is a key endogenous inhibitor of amyloid-β (Αβ) aggregation. In vitro HSA inhibits Aβ fibrillization and targets multiple species along the aggregation pathway including monomers, oligomers, and protofibrils. Amyloid inhibition by HSA has both pathological implications and therapeutic potential, but the underlying molecular mechanism remains elusive. As a first step towards addressing this complex question, we studied the interactions of an Aβ42 monomer with HSA by molecular dynamics simulations. To adequately sample the conformational space, we adapted the replica exchange with solute tempering (REST2) method to selectively heat the Aβ42 peptide in the absence and presence of HSA. Aβ42 binds to multiple sites on HSA with a preference to domain III and adopts various conformations that all differ from the free state. The β-sheet abundances of H14-E22 and A30-M33 regions are significantly reduced by HSA, so are the β-sheet lengths. HSA shifts the conformational ensemble towards more disordered states and alters the β-sheet association patterns. In particular, the frequent association of Q15-V24 and N27-V36 regions into β-hairpin which is critical for aggregation is impeded. HSA primarily interacts with the latter β-region and the N-terminal charged residues. They form promiscuous interactions characterized by salt bridges at the edge of the peptide-protein interface and hydrophobic cores at the center. Consequently, intrapeptide interactions crucial for β-sheet formation are disrupted. Our work builds the bridge between the modification of Aβ conformational ensemble and amyloid inhibition by HSA. It also illustrates the potential of the REST2 method in studying interactions between intrinsically disordered peptides and globular proteins.