Molecular Insights on the Reduction‐Dependent Electronic Modulation of Graphene Oxide Surface Toward Reactivity and Acetylcholinesterase Inhibition of Alzheimer’s Drugs

Assessing the chemistry of drug molecules at nanointerfaces offers opportunities for designing advanced therapeutic materials. The systematic reduction of oxygen-containing functional groups on graphene oxide (GO) surface from 49% to 19% significantly enhances acetylcholinesterase (AChE) inhibition activity of Alzheimer's disease drugs, huperzine A (HUP) and tacrine (TAC) by 10.44% and 27.87%, respectively. Molecular dynamics simulations combined with protein tunnel analysis reveal that shrinking of "bottleneck radius" in the AChE active site gorge due to adsorption on reduced GO surface promotes enhanced AChE inhibition. Additionally, significant increase in antioxidant activity of HUP and TAC (6.94% and 8.81%, respectively). The results are also consistent for the benchmark phenolic and nonphenolic model antioxidant systems represented by gallic acid and α-terpinene, respectively. Notably, highly reduced GO induces a SOMO-HOMO inversion, indicating an extensive electronic reorganization at the interface that leads to the stability of surface-bound radical species. These results establish a direct correlation between the extent of GO surface reduction, electronic structure, and molecular reactivity, providing a mechanistic framework for tuning nano-bio interactions. Looking from the broader perspective, this work offers a rational basis for the design of multifunctional GO-based nanomaterials for applications in catalysis, radical chemistry, and neurotherapeutics.