Ligand detachment dynamics. The removal of surface ligands from nanoclusters is a critical step in enhancing their electrocatalytic activity. Fully ligand-protected nanoclusters, such as Au25(SR)18, are typically considered electrochemically inactive and exhibit significant overpotential during the electrocatalytic process. This inactivity is primarily caused by the passivating effect of the ligands, which block the access of reactants to the metal core and hinder the efficient mass and charge transfer between the nanocluster and the reactants. Consequently, the selective removal of ligands from specific sites on the nanocluster surface is necessary to expose the active sites. Our recent studies have provided valuable insights into the mechanism of partial ligand removal in Au25(SCH3)18 NCs, where the applied reduction potential would induce the spontaneous desulfurization process via breaking the Au-S bonds regardless of the electrolyte environments (acid, neutral or basic condition). Building on these prior findings, we firstly combined the constant potential calculations and AIMD simulations to explore how the presence of surface hydrophilic and hydrophobic ligands affect the stability of Au-S interface under acid electrochemical conditions. We modeled the Au25 NCs with ligands aligned along the z-axis, simulating the system in both explicit water slabs and an implicit solvation environment to accurately capture the realistic electrochemical conditions. Our theoretical model includes hydrophilic [Au25(CH2COOH)18] -and hydrophobic [Au25(CH2CH3)18] -NCs (illustrated in Figure ) placed in the simulation box filled with bulk water at an average density of approximately 1 g cm H2O molecules and one H3O + ion to simulate the acidic environment. To explicitly consider the electrode potential, we manually adjusted the number of extra electrons to control the applied potential U (more details on the constant potential calculations can be found in Supporting Information). Our AIMD simulations at room temperature (300 K) revealed that the -SR ligands on both the [Au25(CH2COOH)18] -and [Au25(CH2CH3)18] -NCs become unstable when subjected to the applied potential. In the dynamic process, the proton from the solvated H3O + ion is attracted and adsorbed onto the sulfur atom, weakening the Au-S bonds. When the potential becomes sufficiently negative, this weakening leads to the complete breakage of the Au-S bonds and the formation of HSR molecule, as illustrated in the AIMD snapshots (Figure , left). Specifically, in the case of [Au25(CH2CH3)18] -NC, the potential (URHE = -1.36 V) was not negative enough to facilitate proton adsorption onto the sulfur atom, leading instead to proton transfer and diffusion into the solvent (details provided in Figure ).