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

The senile plaques of neurotoxic aggregates of A beta protein, deposited extraneuronally, mark the pathological hallmark of Alzheimer's disease (AD). The natural compounds such as omega-3 (omega-3) polyunsaturated fatty acids (PUFAs), which can access blood-brain barrier, are believed to be potential disruptors of preformed A beta fibrils to cure AD with unknown mechanism. Herein, we present the destabilization potential of three omega-3 PUFAs, viz. Eicosapentaenoic acid (EPA), Docosahexaenoic acid (HXA), and alpha-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 beta-sheet content, and disruption of salt bridges and hydrophobic contacts establish the binding of these ligands to A beta 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 A beta 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 A beta 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 A beta 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.