Site-specific drug delivery: Molecular insights into the pH-dependent dissociation of carbon dot-carnosine peptide conjugates via DFT studies

Abstract

This study employs density functional theory (DFT) simulations to investigate the molecular structure and dissociation mechanism of a carbon dot (CD)-conjugated anticancer carnosine peptide (CDP) drug delivery system. Designed for site-specific targeting, this system aims to selectively dissociate in the slightly acidic microenvironments characteristic of cancer sites, thereby facilitating controlled drug delivery. DFT simulations were performed to optimize the geometry and calculate the frequency of the CDP conjugate at varying pH levels, using water (neutral pH, ∼7) and 2,2,2-trifluoroethanol (acidic pH, 5–7) as solvents to mimic the environments of healthy and cancerous cells, respectively. The band gap of the CDP conjugate decreased from 0.153 eV in neutral pH to 0.147 eV in acidic pH, indicating increased reactivity and reduced stability under acidic conditions. This instability was further evidenced by the elongation of bond length from 3.202 Å (neutral pH) to 3.999 Å (acidic pH) and the Gibbs free energy (ΔG), which became positive (3.642 kcal/mol) in acidic conditions, signaling antibonding characteristics. FTIR spectroscopy results supported the dissociation mechanism, with characteristic peaks observed in acidic conditions: CO stretching coupled with N–H bending of the peptide at 1642 cm⁻¹, aromatic C–H vibrations at 1377 cm⁻¹, and O–H stretching vibrations at 3658 cm⁻¹, indicating weakened bonds and potential dissociation. Non-covalent interaction (NCI) calculations revealed that van der Waals interactions significantly contributed to the dissociation of the peptide from the CDP conjugate. Quantum Theory of Atoms in Molecules (QTAIM) analysis highlighted a reduction in electron density at the bond critical point (BCP) in acidic pH, with ΔE decreasing from −3.012 kcal/mol (neutral) to −3.202 kcal/mol (acidic), confirming the reduced stability of the CDP conjugate under acidic conditions. These findings elucidate the stability and dissociation mechanisms of the CDP conjugate in neutral and acidic environments, providing valuable insights for designing effective targeted cancer therapies using this novel drug delivery system.