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Abstract
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 β-amyloid peptide (Aβ). Many of them possess aromatic moieties, suggesting a dominant role for those in interacting with Aβ along various stages of the aggregation process. In this study, we attempt to elucidate whether interactions of such aromatic inhibitors with monomeric Aβ(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 Aβ(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 Aβ(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 Aβ(12-28) reveals differences highlighted by altered populations of a looplike conformer in the presence of inhibitors. We conclude that intrinsic disorder of Aβ persists at the level of binding small molecules and that inhibitors can significantly alter properties of monomeric Aβ via multiple routes of differing specificity.
Highlights
Inhibition of pathogenic protein aggregation by small molecules is poorly understood
We focus on NQTrp, which has the highest affinity for A(12–28) in the molecular dynamics (MD) simulations and is one of the most potent inhibitors of A peptide aggregation in experiments [43]
Five main results emerge from the comparative analysis of MD simulations of A(12–28) alone and in the presence of small molecules that have been shown experimentally to interfere with A peptide self-assembly
Summary
Inhibition of pathogenic protein aggregation by small molecules is poorly understood. We conclude that intrinsic disorder of A persists at the level of binding small molecules and that inhibitors can significantly alter properties of monomeric A via multiple routes of differing specificity. We use molecular dynamics (MD) simulations to analyze 10 different small molecule inhibitors of A peptide aggregation and focus on their influence on the free energy surface of monomeric A(12–28). How does the free energy surface of monomeric A(12–28) change in the presence of small molecules that are known to interfere with oligomerization and/or fibril formation? An analysis of binding frequency and the enhancement of a specific, otherwise transiently populated conformation of A(12–28) in the presence of inhibitors suggests a complex interplay of interfacial effects, trends that can be mapped back to simple physicochemical properties of the primary sequence, and last, highly specific effects that require elucidation by atomistic simulations
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