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 behavior 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, nonprotonated amine -NH2 (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 -NH2, -NH3+, 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, -NH2 (NP), -NH3+ (P), -COOH (NP), and -COO- (DeP) terminations exhibit the most favorable drug-binding characteristics. Except for deprotonated carboxylate systems, curcumin binds more strongly than doxorubicin. Further, drug clustering and spatial organization are governed by dendrimer surface functionality, protonation state, drug loading, and drug-specific interactions. Protonation and higher loading promote drug-drug association, with curcumin and doxorubicin preferentially localizing toward the inner and outer dendrimer regions, respectively. Overall, these findings establish molecular-level relationships between surface functionality, protonation state, dendrimer architecture, and drug-binding behavior, providing design principles for pH-responsive dendrimer nanocarriers with enhanced drug-loading and controlled-release performance.