Insights into Molecular Mechanisms of EGCG and Apigenin on Disrupting Amyloid-Beta Protofibrils Based on Molecular Dynamics Simulations

Abstract

The fibrillization and deposition of amyloid-beta (Aβ) protofibrils are one of the important factors leading to Alzheimer's disease. Molecular dynamics simulations can offer information on intermolecular interaction mechanisms between Aβ protofibrils and Aβ fibrillization inhibitors. Here, in this work, we explore the early molecular mechanisms of (−)-epigallocatechin-3gallate (EGCG) and apigenin on disrupting Aβ42 protofibrils based on molecular simulations. The binding modes of EGCG and apigenin with the Aβ42 protofibril are obtained. Furthermore, we compare the behavioral mechanisms of EGCG and apigenin on disturbing the Aβ42 protofibril. Both EGCG and apigenin are able to decrease the proportion of the β-sheet and bend structures of the Aβ42 protofibril while inducing random coil structures. The results of hydrogen bonds and D23-K28 salt bridges illustrate that EGCG and apigenin have the ability of destabilizing the Aβ42 protofibril. Meanwhile, the van der Waals interactions between the EGCG and Aβ42 protofibril are shown to be larger than that of apigenin with the Aβ42 protofibril, but the electrostatic interactions between apigenin and the Aβ42 protofibril are dominant in the binding affinity. Our findings may help in designing effective drug candidates for disordering the Aβ protofibril and impeding Aβ fibrillization.

Illustrating the Effect of Small Molecules Derived from Natural Resources on Amyloid Peptides

“…Due to the small size of apigenin, it enters into the cavity of Aβ protofibrils, and their association is dominated by electrostatic interactions. On the other hand, hydrophobic interactions play a major role in EGCG-Aβ binding . Apigenin is also an effective inhibitor of α-syn aggregation and inhibits hIAPP fibril formation. , Biflavonoids with double apigenin structures (amentoflavone and bilobetin) display better inhibitory ability against hIAPP aggregation .…”

“…On the other hand, hydrophobic interactions play a major role in EGCG-Aβ binding. 35 Apigenin is also an effective inhibitor of α-syn aggregation and inhibits hIAPP fibril formation. 36,37 Biflavonoids with double apigenin structures (amentoflavone and bilobetin) display better inhibitory ability against hIAPP aggregation.…”

Unveiling How Hydroxytyrosol Destabilizes α-Syn Oligomers Using Molecular Simulations

“…ChemDraw Ultra 16.0 34 was used to create the 2D structure of HT (Figure 1b), which was optimized by Gaussian09 utilizing the Hartree−Fock (HF) theory and a 6-31G(d) basis set. 35 To cover the whole α-Syn trimer, a grid box with dimensions of 126 × 126 × 126 Å 3 was used. For molecular docking, the default settings were assigned and the final result was determined to be the pose with the lowest binding energy.…”

“…As an orthogonal Greek-key-like structure, α-Syn trimer is made up of 63 amino acids having residues 37–99 in each chain. ChemDraw Ultra 16.0 was used to create the 2D structure of HT (Figure b), which was optimized by Gaussian09 utilizing the Hartree–Fock (HF) theory and a 6-31G­(d) basis set . To cover the whole α-Syn trimer, a grid box with dimensions of 126 × 126 × 126 Å 3 was used.…”

Effect of Terahertz Waves on the Structure of the Aβ42 Monomer, Dimer, and Protofibril: Insights from Molecular Dynamics Simulations

“…However, due to available experimental technologies, it is still challenging to systematically visualize the structure and self-assembly process of Aβ42 peptides under various conditions. Molecular simulations, on the contrary, may offer some useful information from the microscopic view, which have been extensively employed in this field. − For example, Fatafta et al performed microsecond-scale molecular dynamics (MD) simulations to explore the dynamic behavior of the Aβ42 dimer in different environments and found that the secondary structure of the Aβ42 dimer exhibited a transition from a random coil to a β-sheet in solution, but it was inhibited to some extent in the presence of lipid bilayers. Man et al reported an all-atom MD simulation study on Aβ42 dimers, trimers, and tetramers.…”