Curcumin Inhibits the Primary Nucleation of Amyloid-Beta Peptide: A Molecular Dynamics Study.

Irini Doytchinova,Mariyana Atanasova,Stefan Ivanov,Evdokiya Salamanova,Ivan Dimitrov

doi:10.3390/biom10091323

Abstract

The amyloid plaques are a key hallmark of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Amyloidogenesis is a complex long-lasting multiphase process starting with the formation of nuclei of amyloid peptides: a process assigned as a primary nucleation. Curcumin (CU) is a well-known inhibitor of the aggregation of amyloid-beta (Aβ) peptides. Even more, CU is able to disintegrate preformed Aβ firbils and amyloid plaques. Here, we simulate by molecular dynamics the primary nucleation process of 12 Aβ peptides and investigate the effects of CU on the process. We found that CU molecules intercalate among the Aβ chains and bind tightly to them by hydrogen bonds, hydrophobic, π–π, and cation–π interactions. In the presence of CU, the Aβ peptides form a primary nucleus of a bigger size. The peptide chains in the nucleus become less flexible and more disordered, and the number of non-native contacts and hydrogen bonds between them decreases. For comparison, the effects of the weaker Aβ inhibitor ferulic acid (FA) on the primary nucleation are also examined. Our study is in good agreement with the observation that taken regularly, CU is able to prevent or at least delay the onset of neurodegenerative disorders.

Highlights

Amyloidogenic peptides and proteins are soluble structures that are able to aggregate into insoluble amyloid fibrils with a characteristic core structure rich in β-sheets [1]
Amylin is involved in the regulation of insulin and glucagon secretion [6], tau protein stabilizes the microtubules in the cells [7], the amyloid-beta peptide controls the synaptic activity [8] and acts as a protective agent against brain infections [9,10], α-synuclein regulates the neurotransmitter release [11], and premalanosome protein (PMEL) forms fibrils in the melanocytes required for the optimal cell function [12]
The five modeled Aβ ensembles—12 Aβ1-42 monomers (10.4 mM), 12 Aβ1-42 monomers + 12 CU molecules (9.3 mM), 12 Aβ1-42 monomers + 36 CU molecules (30.4 mM), 12 Aβ1-42 monomers + 12 ferulic acid (FA) anions (10.3 mM), and 12 Aβ1-42 monomers + 36 FA anions (31.2 mM) (Figure 2)—were simulated in saliva for 1 μs according to the molecular dynamics (MD) protocol described in Models and Methods

Summary

Introduction

Amyloidogenic peptides and proteins are soluble structures that are able to aggregate into insoluble amyloid fibrils with a characteristic core structure rich in β-sheets [1]. Evolutionary, these proteins have appeared in the microorganisms as necessary components of physiological functions such as biofilm formation [2], cell adhesion [3], interactions with host membranes [4], and permeabilization [5]. The triggers that convert the functional amyloids into pathological ones still remain unclear

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