Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

93-POS Board 13 Mechanistic Insights into Modulation of Amyloid Pathways by DNA Intercalators Jasdeep Singh , Bishwajit Kundu. Indian Institute of Technology Delhi, New Delhi, New Delhi, India. Amyloid structures share a sequence independent core consisting of a cross-β spine stabilized through inter-molecular H-bonding networks, with their initial assembly derived by hydrophobic and aromatic interactions. Co-operative balance of similar interactions also confer stability and integrity to DNA duplexes present in living systems. Structural perturbations of both assemblies, by planar molecules or intercalators rely on their ability to interfere with this balance. Although several reports on small molecule based amyloid intervention exist, perturbation of amyloids by planar, DNA intercalating moieties have not been studied yet. The present work investigates detailed mechanism(s) of these hetero-molecular interaction that may modulate amyloid assembly by disturbing the aforesaid interacting forces. Herein, we employed four different DNA intercalators to understand if their non-native hetero-molecular associations could modulate amyloid forming pathways. Through microsecond scale simulations, we show that each molecule individually is capable of interfering with native aggregation landscape of a steric zipper from diabetes associated amyloid precursor protein (hIAPP). Further, the simulation estimates were experimentally tested and validated with other disease associated amyloid systems including gelsolin, prion and lysozyme. Experimental verification using spectroscopic studies and electron microscopy showed that intercalators indeed stabilize monomeric and prefibrillar assemblies, reducing their ability to transform into structured supra-molecular amyloids. Our results conclusively establish dominant role of aromatic associations in diverting course of amyloid assembly process at the expense of stabilizing H-bond networks. Overall, our study provides comprehensive theoretical and experimental insights that would pave ways for designing newer anti-amyloid therapeutics.

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