Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data

and Computer Simulations

Poster Abstracts

130

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.