MICAL-Inspired Chiral Vanadate Nanoclusters Decelerate Actin Dynamics in Live Cells

Actin turnover is a fundamental cellular process essential for cell dynamics, whose control is critical for both medicine and biotechnology. However, conventional small molecules modifying actin turnover scramble the structure of actin filaments and display high cellular toxicity. MICAL enzymes oxidizing methionine (Met) residues in actin can potentially address this challenge, but their large size and multiple required cofactors make MICALs manufacturing and utilization difficult. Here we show that redox-active chiral decavanadate nanoclusters with tartaric acid are capable of site-selective actin modulation, mimicking MICALs, while requiring no cofactors, displaying high biocompatibility and being membrane permeable. Decavanadate nanoclusters serve as atomically precise "nano-enzymes" oxidizing three Met residues in globular actin, including Met-176; the latter inhibits the opening of the backdoor segment and prevents depolymerization of actin filaments. The structure of actin filaments formed after nanocluster treatment revealed no structural disturbances as confirmed by cryo-electron microscopy. The biocompatibility and bioactivity of chiral decavanadate nanoclusters was demonstrated by modulation of actin in living NG108-15 cells. Taking advantage of atomically precise structure of the nanoclusters, we show that their docking into actin can be predicted computationally, indicating the possibility of programmable actin modulation using the tools of nanochemistry.