Ligand steric effects of nano-inhibitors on Aβ fibrillation at the nano-bio interfaces

Amyloid-β (Aβ) fibrillation is a characteristic feature of Alzheimer's disease. Previous studies have identified several interfacial physicochemical factors, including charge, hydrophobicity, and chirality of multi-scaled biostructures, that determine Aβ fibrillation. However, the impact of ligand steric effects on the nano-bio structure in the Aβ fibrillation process remains unclear, which significantly hinders the development of highly efficient nano-inhibitors. Here we constructed four ligands (N-acetyl-L-cysteine (NAC), N-propionyl-L-cysteine (NPC), N-isobutyryl-L-cysteine (NIBC), and N-pivaloyl-L-cysteine (NPVC)) modified Cu2S quantum dots (QDs) with identical core-size (3.6 ± 0.6 nm) to investigate their respective ligand steric effects on Aβ40 fibrillation at nano-bio interface. Our results demonstrated that all four Cu2S QDs inhibited Aβ40 fibrillation in a dose-dependent manner, however, their inhibitory efficiency varied depending on the different steric structures of the ligands employed. NPC-Cu2S QDs exhibited the highest efficiency followed by NIBC-Cu2S QDs, NPVC-Cu2S QDs and NAC-Cu2S QDs at equivalent dosages. Mechanistic studies revealed that these differences in inhibitory efficiency were primarily attributed to the stereoselective interactions between the distinct steric ligands of Cu2S QDs and the electro-positive amino acid residues (R5, K16 and K28), as well as their neighboring residues within Aβ40 sequence. This work provides valuable insights into understanding the ligand steric effects of nano-inhibitors on Aβ fibrillation at nano-bio interfaces and offers guidance for precise regulation of protein fibrillation through customization of appropriate ligand groups.