DFT and MD investigations of doxorubicin-Pertuzumab delivery via PLGA nanocarriers: Thermodynamic stability and optical properties

This study presents a comprehensive computational investigation into the encapsulation and delivery mechanisms of doxorubicin (DOX) and Pertuzumab using biocompatible PLGA nanoparticles, using DFT/MD to decode the molecular interactions, stability, and release dynamics of the system. This targeted approach addresses critical challenges in HER2+ breast cancer therapy by simultaneously overcoming DOX's cardiotoxicity and Pertuzumab's poor tumor penetration. The pairwise interaction energies between PLGA and key residues in Pertuzumab reveal that Asp167, Phe168, His284, and Val169 exhibit the strongest binding affinities, with E Pair values ranging from 11.50 to 23.80 kcal·mol -1 , indicating their critical role in stabilizing the nanocomplex through hydrogen bonding, van der Waals forces, and electrostatic interactions. DOX encapsulation within the PLGA-Pertuzumab complex is governed by multivalent interactions, including hydrophobic contacts with Val169 and Leu372 at distances of 3.8–5.0 Å, charge-assisted hydrogen bonds with Glu154 and Asp167 at 2.9–3.3 Å, and π-anion stacking (aromatic ring-electrostatic interactions between DOX's anthraquinone and carboxylates) contributing significantly to overall binding energy. Energy decomposition reveals binding is driven by van der Waals (ΔE vdw : -38.45 kcal/mol) and electrostatic (ΔE ele : -85.32 kcal/mol) components, representing 79% of ΔG bind . Electronic structure calculations show minimal perturbation to DOX’s pharmacophore upon PLGA complexation, preserving its cytotoxic activity with a nearly unchanged HOMO-LUMO gap of 69 kcal/mol and enhanced solubility due to a slight increase in dipole moment from 8.5 to 9.1 D. MD simulations over 20 ns confirm the structural integrity of the DOX@Pertuzumab-PLGA nanocomplex, with RMSD values stabilizing below 1.5 Å for all components after 12 ns, demonstrating dynamic stability under physiological conditions. These findings provide a rational framework for designing antibody-chemotherapeutic co-delivery systems, offering insights into optimizing polymer-drug interactions for improved therapeutic efficacy and reduced off-target toxicity in HER2-positive breast cancer treatment.