Disordered Binding of Small Molecules to Aβ(12-28)

In recent years, an increasing number of small molecules and short peptides have been identified that interfere with aggregation and/or oligomerization of the Alzheimer beta-amyloid peptide (A beta). Many of them possess aromatic moieties, suggesting a dominant role for those in interacting with A beta along various stages of the aggregation process. In this study, we attempt to elucidate whether interactions of such aromatic inhibitors with monomeric A beta(12-28) point to a common mechanism of action by performing atomistic molecular dynamics simulations at equilibrium. Our results suggest that, independently of the presence of inhibitors, monomeric A beta(12-28) populates a partially collapsed ensemble that is largely devoid of canonical secondary structure at 300 K and neutral pH. The small molecules have different affinities for A beta(12-28) that can be partially rationalized by the balance of aromatic and charged moieties constituting the molecules. There are no predominant binding modes, although aggregation inhibitors preferentially interact with the N-terminal portion of the fragment (residues 13-20). Analysis of the free energy landscape of A beta(12-28) reveals differences highlighted by altered populations of a looplike conformer in the presence of inhibitors. We conclude that intrinsic disorder of AB persists at the level of binding small molecules and that inhibitors can significantly alter properties of monomeric AB via multiple routes of differing specificity.