Tuning Protein-Nanoparticle Interfacial Interactions via Zwitterionic Surface Functionalization: A Molecular Dynamics...

Understanding nanoparticle-protein interactions is crucial for designing biocompatible nanocarriers. Here, we performed atomistic molecular dynamics simulations to investigate the binding of human serum albumin (HSA) with carbon quantum dot (CQD)-based nanoparticles functionalized with poly(amidoamine) (PAMAM) dendrimers modified by zwitterionic carboxybetaine acrylamide (CBAA). Three systems with 0% (M0), 50% (M50), and 90% (M90) CBAA modifications were constructed to assess the effect of surface zwitterion density on protein adsorption, hydration, and structural stability. The fully modified M90 nanoparticles exhibited the weakest HSA binding due to reduced electrostatic attraction and steric shielding as well as the formation of a stable, dense hydration layer that hindered protein attachment. Across all systems, HSA retained its secondary structure, confirming its structural compatibility. These findings provide molecular insights into the antifouling mechanisms of CBAA-modified CQD-PAMAM nanocarriers and guide their rational design for enhanced biocompatibility.