Destabilization of Aβ fibrils by omega-3 polyunsaturated fatty acids: a molecular dynamics study

Abstract

The senile plaques of neurotoxic aggregates of Aβ protein, deposited extraneuronally, mark the pathological hallmark of Alzheimer’s disease (AD). The natural compounds such as omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), which can access blood–brain barrier, are believed to be potential disruptors of preformed Aβ fibrils to cure AD with unknown mechanism. Herein, we present the destabilization potential of three ω-3 PUFAs, viz. Eicosapentaenoic acid (EPA), Docosahexaenoic acid (HXA), and α-linolenic acid (LNL) by molecular dynamics simulation. After an initial testing of 300 ns, EPA and HXA have been considered further for extended production run time, 500 ns. The increased value of root mean square deviation (RMSD), radius of gyration, and solvent-accessible surface area (SASA), the reduced number of H-bonds and β-sheet content, and disruption of salt bridges and hydrophobic contacts establish the binding of these ligands to Aβ fibril leading to destabilization. The polar head was found to interact with positively charged lysine (K28) residue in the fibril. However, the hydrophobicity of the long aliphatic tail competes with the intrinsic hydrophobic interactions of Aβ fibril. This amphiphilic nature of EPA and HXA led to the breaking of inherent hydrophobic contacts and formation of new bonds between the tail of PUFA and hydrophobic residues of Aβ fibril, leading to the destabilization of fibril. The Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) results explain the binding of EPA and HXA to Aβ fibril by interacting with different residues. The destabilization potential of EPA and HXA establishes them as promising drug leads to cure AD, and encourages prospecting of other fatty acids for therapeutic intervention in AD. Communicated by Ramaswamy H. Sarma