Delineating the tryptophan-galactosylamine conjugate mediated structural distortions in Aβ42 protofibrils.

Amyloid-β (Aβ) fibrillation into neurotoxic soluble oligomers and mature fibrils is mainly responsible for the etiology of Alzheimer's disease (AD). A recent study revealed 61% disaggregation of the pre-formed Aβ42 fibrils upon incubating with a highly soluble tryptophan-galactosylamine conjugate, WGalNAc. WGalNAc displayed no toxicity and increased the viability of SH-SY5Y cells up to 62.9 ± 2% with an EC50 value of 2.3 μM against Aβ42 pre-formed fibrils. However, the key interactions and disruptive mechanism of WGalNAc against Aβ fibrils remain elusive. Thus, mechanistic insights into the disruptive potential of WGalNAc against Aβ42 protofibrils (PDB: 5OQV) were examined using molecular dynamics (MD) simulations. The molecular docking depicted a favourable binding energy (-6.60 kcal mol-1) and interaction of WGalNAc with the central hydrophobic core (CHC) region of chain A of the 5OQV protofibril. The MD simulations depicted that WGalNAc disrupted the contacts among Ala2, Phe4, Leu34, and Val36 in the hydrophobic core 1 of the 5OQV protofibril responsible for maintaining the stability of the LS-shaped 5OQV protofibril. WGalNAc binds favourably to the 5OQV protofibril (ΔGbinding = -21.76 ± 2.40 kcal mol-1) with a significant contribution from the van der Waals interaction term. Notably, the binding affinity between the neighbouring chains of the 5OQV protofibril was significantly reduced from -134.31 ± 11.12 to -121.88 ± 1.95 kcal mol-1 upon the incorporation of WGalNAc, which is consistent with the ThT kinetic results that revealed disaggregation of the pre-formed Aβ42 fibrils upon incubating with WGalNAc. The in silico ADMET properties of WGalNAc showed its ability as a promising therapeutic candidate due to its blood-brain barrier (BBB) permeability, extended half-life, and non-toxic profile. The MD simulations illuminated the binding interactions of WGalNAc with the 5OQV protofibril and provided mechanistic insights into the WGalNAc-mediated structural distortions in the 5OQV protofibril.