Unveiling the pH-Responsive Mechanisms of the Carbon Dot–Proximicin-A Peptide Conjugate for Targeted Cancer Therapy Using Density Functional Theory

This study investigates the pH-responsive dissociation mechanism of carbon dot (CD) conjugated with the anticancer peptide proximicin-A (PROXI) using density functional theory (DFT) simulations. The CD@PROXI system, designed for targeted cancer therapy, releases the drug in acidic environments typical of cancer sites. DFT simulations, with the B3LYP-D3BJ functional and 6-311G (d, p) basis set, optimized the conjugate’s geometry under neutral and acidic conditions. The focus was on the pH-sensitive C=N bond, existing in two protonation states. Key parameters evaluated included the HOMO-LUMO gap, bond length, IR spectroscopy, non-covalent interaction (NCI), electron localization function (ELF), density of states (DOSs), and electrostatic potential (ESP). Under neutral pH, the system showed stability with a HOMO-LUMO gap of 3.22 eV, indicating low reactivity. In acidic pH, this gap decreased to 0.40 eV, suggesting higher reactivity and potential for drug release. IR spectroscopy indicated weakened C=N bonds in acidic conditions, with bond length increasing from 1.288 Å to 1.324 Å. NCI analysis revealed increased van der Waals interactions, supporting bond weakening. ELF analysis showed electron localization at reactive sites, while DOS profiles and ESP maps highlighted distinct electronic states and potential dissociation regions in acidic conditions. These findings confirm the potential of CD@PROXI for targeted cancer therapy, with drug release triggered by the acidic tumor microenvironment.