Interfacial metal atoms of metallic nano-chaperones on modulating amyloid fibrillation

Synthetic metallic nano-chaperones possessing biomolecular chaperone functions hold great promise as candidates for modulating protein conformation. Despite extensive research, the involvement and mechanisms of interfacial metal atoms in metallic nano-chaperones on modulating protein conformation remain elusive, significantly hindering the development of high-performance metallic nano-chaperones. In this study, interfacial atomically precise metal nanoclusters (Au25, Au24Ag1, Au24Cd1, Au24Cu1) modified with the same ligand 3-Mercaptopropionic acid (MPA) were prepared as a model to systematically investigate their modulation effects on Aβ40 fibrillation. All-atom molecular dynamics simulation suggested that the interfacial doped metal atoms (Cu, Cd and Ag) can influence the folding of Aβ40 in contact with them through weak interactions including vander-Waals forces and electrostatic interactions. Isothermal titration calorimetry results further revealed that the interaction of Au24Cu1 to Aβ40 was 1.76, 2.09, 16.67 times larger than those of Au24Cd1, Au24Ag1 and Au25, respectively. Consequently, these differential interactions translated into different modulating effects of metallic nano-chaperones on Aβ folding and even subsequent fibrillation, with the order of effectiveness being Au24Cu1 > Au24Cd1 > Au24Ag1 > Au25. This work provides microscopic molecular insights into the identity of interfacial metal atoms on metallic nanoclusters and offers guidelines for customizing metallic nano-chaperones by manipulating their interfacial metal atoms.