Insights into the Interactions Between Monolayer‐Protected Metal Nanoclusters and Amyloid‐β Fibrils

Abstract

Monolayer‐protected atomically precise metal nanoclusters (MPCs) have attracted significant attention from the scientific community because of their unique structural and physicochemical properties. In addition to their diverse applications in bioimaging and biosensing, water‐soluble MPCs have shown promise as nanotherapeutics. However, in‐depth knowledge of how MPCs act as therapeutic agents remained unexplored. In this work, the inhibition mechanism of amyloid fibril growth by atomically precise gold nanoclusters functionalized with positively charged ligands, 8‐MTA (mercaptooctyltrimethylammonium) and polyphenol‐based ligands, ‐alkyl derivative of epigallocatechin‐3‐gallate (EGCG) is investigated using extensive all‐atom molecular dynamics simulations. The simulations reveal that ligand‐coated small gold nanoclusters bind to different external sides of an amyloid fibril and stipulate its secondary structure content. Non‐covalent interactions such as electrostatic, van der Waals, –, and hydrogen bonding interactions help bind the nanoclusters in the various regions of amyloid fibril and thereby exert conformational changes on the peptides in the fibril. The pertinent atomistic insights obtained from this work will spur the design of ligand‐functionalized nanoclusters as nanodrugs that can potentially inhibit amyloid fibril growth connected to Alzheimer's and other neurodegenerative diseases.