Modulation of Aβ Aggregation by Aβ-derived Fragment Peptide: A molecular Dynamics Study

Abstract

The self–aggregation of amyloid-β (Aβ42) into β–sheets is considered to be responsible for the onset of Alzheimer’s Disease (AD), a neurodegenerative disease with no clinically accepted treatment. The N‒terminal (16KLVFF20) is identified as a self‒recognition region and the central hydrophobic core (CHC) which is crucial for the formation and stabilization of the β– sheets. Mallesh et al. have recently reported KLLFF, produced by single point mutation by replacing Val18 in KLVFF with leucine KLLFF as a potential inhibitor against Aβ aggregation. The mechanism by which KLLFF hinders Aβ aggregation remains an enigma. To gain insights into this inhibitory mechanism, molecular dynamics (MD) simulations have been performed. The molecular docking was performed using AutoDock Vina which predicted a favourable binding energy of ‒5.2 kcal/mol for Aβ42–KLLFF complex. The MDsimulations depicted enhanced structural stability for Aβ42 in the presence of KLLFF. The presence of KLLFF remarkably prevented the β‒sheet formation by reducing the side‒chain contacts at the C‒ terminal, Gly33‒Val40 of Aβ42. According to the per residue binding energy Phe4, Arg5, Val12, His13, Val18 and Phe19 contributed maximum to binding of Aβ42 with KLLFF. KLLFF further reduced the intramolecular hydrogen bonds of Aβ42, therebystabilizing the native of structure Aβ42. Understanding the inhibitory mechanism of KLLFF against Aβ42 holds great promise for the development of potent drugs to combat AD. Such insights could pave the way for more effective treatments against AD.