DFT-guided charge-state engineering of gold clusters for levodopa recognition: fundamental principles for drug delivery applications

Abstract

Rational design of gold-based nanocarriers for neurotherapeutics requires atomic-scale understanding of drug-material interactions. Density functional theory calculations were performed to investigate levodopa (L-DOPA) adsorption on small gold clusters (Au₂–Au₄) with cationic, neutral, and anionic charges, with additional validation on a larger Au₁₀ cluster using multiple low-energy isomers. Binding free energies (ΔG_bind), charge transfer, and electronic descriptors were determined in gas and aqueous phases. Adsorption strength is strongly dependent on cluster charge. Cationic clusters exhibit the strongest binding, with ΔG_bind ranging from −59.7 to −41.7 kcal mol⁻¹ in the gas phase and −46.6 to −27.4 kcal mol⁻¹ in water, driven by high electrophilicity and significant ligand-to-metal charge transfer (0.66–0.82 e). Neutral clusters show moderate and adaptable binding (ΔG_bind = −28.3 to −11.1 kcal mol⁻¹), with coordination switching between Au–N and Au–O depending on ligand protonation state. Anionic clusters exhibit weak or unfavourable interactions (ΔG_bind = +1.8 to +5.0 kcal mol⁻¹). These charge-dependent trends are preserved across cluster sizes and solvation environments, and are further supported by the Au₁₀ validation, indicating robustness of the observed behaviour. The computed binding energies fall within reported ranges for amino acid adsorption on gold surfaces. From these results, three design principles emerge: (i) cationic or electronically soft gold clusters maximize binding stability; (ii) neutral clusters enable tunable adsorption behaviour; and (iii) anionic clusters are unfavourable for stable conjugation. By elucidating the electronic determinants of Au–L-DOPA interactions, this work provides fundamental insights into charge-controlled binding mechanisms that can guide the rational design of gold-based nanocarriers for neurotherapeutic applications.