DNA intercalators as amyloid assembly modulators: mechanistic insights

Abstract

Amyloid assemblies are stabilized through inter-molecular H-bonding with initial structural organizations governed by extensive hydrophobic and π-stacking interactions. Apparently, the structural integrity and stability of DNA duplexes are also governed by a cooperative balance of similar interactions. Structural perturbations in both amyloids and DNA by planar molecules or intercalators essentially rely on their ability to interfere with this balance. However, poor information on amyloid interference mechanisms by intercalators has subjected researchers to undertake random trials with such anti-amyloidogenic agents. Here, we employed four different classes of DNA intercalators to investigate if their non-native, hetero-aromatic associations could modulate the amyloid aggregation pathway. We utilized micro-second scale MD simulations using the steric-zipper structure of the diabetes associated amylin fragment to identify such associations and their plausible role in subjugating higher order assemblies. The simulation estimates were experimentally validated and extended to other disease-associated amyloid systems including gelsolin, prion and lysozyme. We find that the intercalators essentially stabilize monomeric and prefibrillar assemblies, reducing their ability to transform into structured supramolecular structures. Our results conclusively establish the dominant role of aromatic-associations in diverting the course of the amyloid assembly process at the expense of stabilizing H-bonding networks. Overall this report presents comprehensive experimental and theoretical insights on the regulation of amyloidogenesis by aromatic planar moieties.