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

This bioRxiv preprint investigates how surface functionality and protonation state govern the structural dynamics, hydration, and drug binding of dendrimers intended for drug delivery. All-atom molecular dynamics 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 various protonation states.

Protonation of tertiary branch-point amines caused dendrimer expansion, increased internal porosity and hydration, and enhanced structural fluctuations in both families. In contrast, non-protonated amine and carboxylic acid terminated dendrimers, as well as deprotonated carboxylate systems, retained compact conformations. Sugar-functionalized dendrimers (β-galactose-terminated PETIM and D-glucose-terminated PAMAM) were the most hydrated and structurally rigid, while amine-terminated dendrimers exhibited the greatest conformational dynamics. PAMAM dendrimers with -NH2, -NH3+, and -COO- groups were generally more hydrated than PETIM counterparts, but β-galactose-terminated PETIM dendrimers were more hydrophilic than D-glucose-terminated PAMAM dendrimers. N-core PETIM dendrimers adopted more compact and spherical conformations than equivalent O-core PETIM dendrimers.

Drug-binding simulations showed that curcumin binding was dominated by van der Waals interactions, while doxorubicin complexation was primarily electrostatic. Among the surface functionalities tested, -NH2, -NH3+, -COOH, and -COO- terminations showed the most favorable drug-binding characteristics. Curcumin generally bound more strongly than doxorubicin, except in deprotonated carboxylate systems. The findings establish molecular-level relationships between surface functionality, protonation state, dendrimer architecture, and drug binding, providing design principles for pH-responsive dendrimer nanocarriers with enhanced drug loading and controlled release.