Black phosphorus (BP) nanomaterials are promising for biomedical applications owing to their extraordinary biodegradability. Although previous research has demonstrated changes in the physicochemical properties of BP due to degradation, the impact of degradation on BP interactions with biological systems remains unclear. In this study, we designed a set of BP nanomaterials with varying degrees of degradation, including pristine BP nanosheet, BP oxide, BP quantum dots, and phosphates, to investigate their interactions with centrosome polo-like kinase 1 (PLK1), a potential target for BP in inhibiting mitosis. Molecular dynamics simulations identified distinctive modes of interactions, unveiling the nonmonotonic relationship between the BP degradation and its effectiveness in suppressing PLK1. Pristine BP can bind to the polo-box domain (PBD) of PLK1, but these interactions were relatively weak and caused minor perturbations in the PBD’s structure. When BP undergoes oxidation, it generates phosphate groups that enhance the binding of PBD. These interactions result in the distortion of the PBD’s active pocket through a lever-like mechanism. As degradation progresses further, smaller BP quantum dots are formed. These quantum dots can specifically recognize and occupy the PBD’s pocket, thereby disrupting the binding of natural phosphopeptide necessary for activation. The final degradation products of BP include phosphates, which have a negligible effect on the structure and function of PBD. These findings offer new molecular-level insights into how the bioactivity of BP can be modulated through degradation, which will be instrumental in guiding the development of safer and more efficient biomedical applications.

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