This study used all-atom molecular dynamics simulations to interrogate how surface functionality and pH (via protonation states) determine structural dynamics, hydration, and drug-binding behavior in two widely studied dendrimer families: PETIM and PAMAM. The simulations encompassed multiple dendrimer generations (PAMAM G1–G5; PETIM G2–G6), two core chemistries (O-core and N-core architectures), and terminal groups including amine, carboxylic acid, and sugar moieties. Protonation states of tertiary branch-point amines and terminal groups were explicitly considered to model pH-dependent behavior.
All-atom MD simulations were performed across the set of dendrimer systems described above. Systems were functionalized with terminal groups in different protonation states: protonated tertiary amines and terminal -NH3+ (P), non-protonated amines -NH2 (NP), non-protonated carboxylic acids -COOH (NP), and deprotonated carboxylates -COO- (DeP). Sugar-terminated dendrimers included β-galactose for PETIM and D-glucose for PAMAM. Two representative drug molecules—curcumin and doxorubicin—were simulated in complexation studies to probe the chemical determinants of loading.
A central finding is that protonation of tertiary branch-point amines promotes dendrimer expansion. Protonated systems adopt more open conformations with increased internal porosity and higher hydration levels. Protonation also enhances structural fluctuations in both PETIM and PAMAM families, indicating greater conformational mobility under acidic/protonating conditions. By contrast, non-protonated terminal chemistries (both -NH2 and -COOH) and deprotonated carboxylate (-COO-) systems retain comparatively compact conformations with reduced dynamic fluctuations.
Sugar-terminated dendrimers were identified as the most hydrated and the most structurally rigid among the surface chemistries studied. Specifically, β-galactose-terminated PETIM and D-glucose-terminated PAMAM display high hydration but relatively low conformational variability. Amine-terminated dendrimers show the largest conformational dynamics, consistent with a more flexible surface and interior.
The study reports family-level differences in hydration: PAMAM dendrimers bearing -NH2, -NH3+, and -COO- terminal groups are generally more hydrated than corresponding PETIM dendrimers. An exception is that β-galactose-terminated PETIM dendrimers are more hydrophilic than D-glucose-terminated PAMAM dendrimers, indicating sugar termination can outweigh backbone-specific hydration trends.
Within the PETIM series, the choice of core chemistry affected global conformation. N-core PETIM dendrimers were reported to adopt more compact and spherical conformations than equivalent O-core PETIM dendrimers, demonstrating that core identity can modulate overall shape and compactness independently of terminal chemistry and protonation.
Drug-binding simulations distinguished two dominant interaction modes for the test compounds. Curcumin binding to dendrimers is described as being dominated by van der Waals interactions, indicating hydrophobic packing and close-contact stabilization are central to curcumin complexation. In contrast, doxorubicin complexation is driven primarily by electrostatic interactions, consistent with its charged character and sensitivity to the protonation state and surface charge of the dendrimer.
Across the simulated surface chemistries, several terminal group/protonation combinations exhibited the most favorable drug-binding characteristics: non-protonated amine (-NH2, NP), protonated amine (-NH3+, P), non-protonated carboxylic acid (-COOH, NP), and deprotonated carboxylate (-COO-, DeP). Except for the deprotonated carboxylate systems, curcumin generally bound more strongly than doxorubicin in these simulations. This indicates that both hydrophobic and electrostatic contributions are important and that relative drug affinity depends on the interplay between drug chemistry and dendrimer surface state.
The molecular-level relationships identified—linking surface functionality, protonation state, dendrimer architecture, hydration, and drug-binding mode—provide practical design principles for engineering pH-responsive dendrimer nanocarriers. Key implications reported in the work include:
Protonation can be used intentionally to expand dendrimer interiors and increase porosity and hydration, potentially improving loading of hydrophobic drugs that rely on internal cavities.
Surface sugars confer high hydration and rigidity, which may favor stability and circulation but could reduce conformational adaptability for drug encapsulation.
Selecting terminal chemistry according to the intended drug—favoring surfaces that provide van der Waals environments for hydrophobic molecules like curcumin or charged surfaces for electrostatically favored drugs like doxorubicin—can improve loading efficiency.
Core chemistry (N-core vs O-core) and dendrimer generation influence overall compactness and shape and should be considered alongside terminal group selection for optimized carrier behavior.
Collectively, these observations suggest routes to tune loading versus release properties by manipulating pH sensitivity, terminal functionality, and core architecture.
This summary is drawn from the abstract of a preprint. The authors state these are all-atom MD results across multiple generations, surface terminations, and protonation states, and that supplementary material is available. Detailed numerical results, simulation parameters, sampling times, specific binding energies, and methodological settings are not provided in the abstract and should be consulted in the full manuscript and supplementary files. The preprint has not been certified by peer review.