Surface Functionality and pH Govern Structural Dynamics and Drug Binding in PETIM and PAMAM Dendrimers

Surface functionality and pH play a decisive role in governing the structural dynamics, hydration, and drug-binding behaviour of dendrimers. Here, all-atom molecular dynamics (MD) simulations were performed on five generations of PAMAM (G1-G5) and PETIM (G2-G6) dendrimers with O-core and N-core architectures, functionalized with amine, carboxylic acid, or sugar terminal groups under different protonation states. Protonation of the tertiary branch-point amines expands the dendrimer structure, increases internal porosity and hydration, and enhances structural fluctuations across both families. In contrast, non-protonated amine −NH ₂ (NP) and carboxylic acid −COOH (NP) terminated dendrimers, together with deprotonated carboxylate-COO ⁻ (DeP) systems, retain comparatively compact conformations. Sugar-functionalized dendrimers (β-galactose-terminated PETIM and D-glucose-terminated PAMAM) are most hydrated and structurally rigid, whereas amine-terminated dendrimers exhibit the greatest conformational dynamics. PAMAM dendrimers with −NH ₂ , −NH ₃ ⁺ , and −COO ⁻ terminal groups are generally more hydrated than their PETIM counterparts. However, β-galactose-terminated PETIM dendrimers are more hydrophilic than D-glucose-terminated PAMAM dendrimers. N-core PETIM dendrimers also adopt more compact and spherical conformations than equivalent O-core PETIM dendrimers. Drug-binding MD simulations show that curcumin binding is dominated by van der Waals (vdW) interactions, whereas doxorubicin complexation is primarily driven by electrostatic interactions. Among the investigated surface functionalities, −NH ₂ (NP), −NH ₃ ⁺ (P), −COOH (NP), and −COO ⁻ (DeP) terminations exhibit the most favourable drug-binding characteristics. Except for deprotonated carboxylate systems, curcumin binds more strongly than doxorubicin. Overall, these findings establish molecular-level relationships between surface functionality, protonation state, dendrimer architecture, and drug-binding behaviour, providing design principles for pH-responsive dendrimer nanocarriers with enhanced drug-loading and controlled-release performance.