The Atomic Level Interaction of Polyphenols with the Aβ Oligomer Aggregate, A Molecular Dynamic Guidance for Rational Drug Design

This chapter gives an overview of the molecular dynamic simulation’s application in elucidating the mechanisms by which polyphenolic compounds inhibit aggregation of peptides related to Alzheimer’s disease. It opens with a discussion on amyloid proteins and their relation to amyloid diseases such as Alzheimer’s and Parkinson’s diseases, and amyloid formation inhibition by polyphenols. The underlying theories of MD are then outlined. This is followed by a literature review of the molecular dynamic studies on the mechanism of aggregation inhibitor effect of polyphenols. We present our studies of Aβ aggregates interaction with polyphenols, their effect on destabilizing the aggregate and the MMPBSA (Molecular Mechanics Poisson-Boltzmann) binding free energy analysis of the Aβ protofibril with polyphenolic compounds. Comparative molecular simulations establish molecular interaction and inhibitory effect of polyphenols. The hydrophobic interaction of the polyphenols with Aβ aggregates was found to play a critical role in both interaction and destabilizing the aggregate. The interaction energy calculated using MMPBSA of the polyphenol/Aβ fibril complex is in good agreement with experimentally derived maximal inhibitory concentration (IC 50 ) values. The significant structural alterations are the loss of a stabilizing hydrophobic interaction at the interface of the double layer. The main effect of polyphenols is the induction of sizable destabilization in native fibril structure. These structural insights may serve as a molecular guide for further rational drug design of effective inhibitors targeting fibril formation in Alzheimer’s disease. Finally, we present the future outlook for a computational approach in the search for and designing of small molecule amyloid aggregation inhibitors.