Enhanced stability of a disaggregated Aβ fibril on removal of ligand inhibits refibrillation: An all atom Molecular Dynamics simulation study.

The extraneuronally deposited senile plaques, composed of neurotoxic aggregates of Aβ fibril, define Alzheimer's disease (AD). Natural compounds have been tested for their destabilization potential on Aβ fibril, thereby curing AD. However, the resultant destabilized Aβ fibril, needs to be checked for its irreversibility to the native organized state after removal of the ligand. Herein, we assessed the stability of a destabilized fibril after the ligand (ellagic acid represented as REF) is removed from the complex. The study has been conducted via Molecular Dynamics (MD) simulation of 1 μs for both Aβ-Water (control) and Aβ-REF″ (test or REF removed) system. The increased value of RMSD, R, SASA, lower β-sheet content and reduced number of H-bonds explains enhanced destabilization observed in Aβ-REF″ system. The increased inter-chain distance demonstrates breaking of the residual contacts, testifying the drift of terminal chains from the pentamer. The increased SASA along with the ∆G(polar solvation energy) accounts for the reduced interaction amongst residues, and more with solvent molecules, governing irreversibility to native state. The higher Gibb's free energy of the misaligned structure of Aβ-REF″ ensures irreversibility to the organized structure due to its inability to cross such high energy barrier. The observed stability of the disaggregated structure, despite ligand elimination, establishes the effectiveness of the destabilization technique as a promising therapeutic approach towards treating AD.