Structural Molecular Dynamics Studies on Polyamidoamine Dendrimers for a Therapeutic Application:  Effects of pH and Generation

Lee, Inhan; Athey, Brian D.; Wetzel, Arthur W.; Meixner, Walter; Baker, James R.

doi:10.1021/ma010354q

Cited by 276 publications

(293 citation statements)

References 30 publications

(46 reference statements)

Supporting

Mentioning

267

Contrasting

Unclassified

Order By: Relevance

“…This is consistent with previous findings that the radius of gyration of PAMAM increases (swollen) at low pH. 8,29 The time evolution of normalized C d (t) for water in the neutral, unprotonated PAMAM solutions is depicted in Figure 3, parts a and b, and those of surface water and buried water around PAMAM at different protonation levels are compared in Figure 3, parts c-f. The water relaxation is determined by …”

Section: Definition Of Water Regimessupporting

confidence: 89%

See 1 more Smart Citation

Dynamics and Thermodynamics of Water in PAMAM Dendrimers at Subnanosecond Time Scales

2005

View full text Add to dashboard Cite

Atomistic molecular dynamics simulations are used to study generation 5 polyamidoamine (PAMAM) dendrimers immersed in a bath of water. We interpret the results in terms of three classes of water: buried water well inside of the dendrimer surface, surface water associated with the dendrimer-water interface, and bulk water well outside of the dendrimer. We studied the dynamic and thermodynamic properties of the water at three pH values: high pH with none of the primary or tertiary amines protonated, intermediate pH with only the primary amines protonated, and low pH with all amines protonated. For all pH values we find that both buried and surface water exhibit two relaxation times: a fast relaxation (∼1 ps) corresponding to the libration motion of the water and a slow (∼20 ps) diffusional component related to the escaping of water from one domain to another. In contrast for bulk water the fast relaxation is ∼0.4 ps while the slow relaxation is ∼14 ps. These results are similar to those found in biological systems, where the fast relaxation is found to be ∼1 ps while the slow relaxation ranges from 20 to 1000 ps. We used the 2PT MD method to extract the vibrational (power) spectrum and found substantial differences for the three classes of water. The translational diffusion coefficient for buried water is 11-33% (depending on pH) of the bulk value while the surface water is about 80%. The change in rotational diffusion is quite similar: 21-45% of the bulk value for buried water and 80% for surface water. This shows that translational and rotational dynamics of water are affected by the PAMAM-water interactions as well as due to the confinement in the interior of the dendrimer. We find that the reduction of translational or rotational diffusion is accompanied by a blue shift of the corresponding libration motions (∼10 cm -1 for translation, ∼35 cm -1 for rotation), indicating higher local force constants for these motions. These effects are most pronounced for the lowest pH, probably because of the increased rigidity caused by the internal charges. From the vibrational density of states we also calculate the enthalpies and entropies of the various waters. We find that water molecules are enthalpically favored near the PAMAM dendrimer: energy for surface water is ∼0.1 kcal/mol lower to that in the bulk, and ∼0.5-0.9 kcal/mol lower for buried water. In contrast, we find that both the buried and surface water are entropically unfavored: buried water is 0.9-2.2 kcal/mol lower than the bulk while the surface water is 0.1-0.2 kcal/mol lower. The net result is a thermodynamically unfavored state of the water surrounding the PAMAM dendrimer: 0.4-1.3 kcal/mol higher for buried water and 0.1-0.2 kcal/mol for surface water. This excess free energy of the surface and buried waters is released when the PAMAM dendrimer binds to DNA or metal ions, providing an extra driving force.

show abstract

Section: Definition Of Water Regimessupporting

confidence: 89%

“…At low pH (∼5), all the 128 primary amines and 126 tertiary amines are protonated. 29 For protonated PAMAM dendrimers, the protons are added before immersing them into water. Short minimization was performed to relax the added proton and its neighboring atoms.…”

Section: Computational Detailsmentioning

confidence: 99%

Dynamics and Thermodynamics of Water in PAMAM Dendrimers at Subnanosecond Time Scales

2005

View full text Add to dashboard Cite

show abstract

“…13,31 Due to the increased availability of space in the dendrimer's interior, water molecules can penetrate even at distances near the center of mass, assuming an almost constant profile characterized by a value close to the density of bulk water.…”

Section: Resultsmentioning

confidence: 99%

“…[7][8][9] A particular class of such moleculessnamely, poly(amidoamine) dendrimers (PAMAM)shas been widely considered for biomedical applications. Properties such as biocompatibility, 10 water solubility, versatility in modifying their functional groups, 11 and responsiveness of their conformational properties to an aqueous environment 12,13 render these molecules appropriate for such uses. These attributes enable PAMAM dendrimers to enhance drug solubilization and to facilitate the transport and the controlled release of complexed pharmaceutical and biological molecules at targeted sites.…”

Section: Introductionmentioning

confidence: 99%

Association of a Weakly Acidic Anti-Inflammatory Drug (Ibuprofen) with a Poly(Amidoamine) Dendrimer as Studied by Molecular Dynamics Simulations

Tanis

Karatasos

2009

J. Phys. Chem. B

View full text Add to dashboard Cite

In this work, we report results from fully atomistic molecular dynamics simulations regarding the associative behavior of a third-generation poly(amidoamine) dendrimer with ibuprofen, a weakly acidic nonsteroidal anti-inflammatory drug, in aqueous solutions and at different pH conditions. Employing a combined static and dynamic approach, we describe the specifics of the complexation/encapsulation of the drug within the dendritic structure. In addition, information regarding the dynamic behavior is provided for the self-and the collective motion of the drug molecules. The detail afforded by the present molecular-level description of the relevant associative mechanisms (i.e., electrostatic complexation, hydrogen-bonding), provides a deeper insight for the interpretation of recent experimental findings regarding the behavior of dendrimer/ibuprofen systems in an aqueous environment.

show abstract

“…42 It has been shown that at pH values between 7 and 8, only dendrimer primary amines are protonated. 43,44 Therefore, we used this convention in modeling the dendrimers at neutral pH used in the experiment. The dendrimers were then added to the trans side of αHL pore at a distance equivalent to twice the radius of gyration of dendrimer.…”

mentioning

confidence: 99%

Dendrimers in Nanoscale Confinement: The Interplay between Conformational Change and Nanopore Entrance

2015

View full text Add to dashboard Cite

Hyperbranched dendrimers are nanocarriers for drugs, imaging agents, and catalysts. Their nanoscale confinement is of fundamental interest and occurs when dendrimers with bioactive payload block or pass biological nanochannels or when catalysts are entrapped in inorganic nanoporous support scaffolds. The molecular process of confinement and its effect on dendrimer conformations are, however, poorly understood. Here, we use single-molecule nanopore measurements and molecular dynamics simulations to establish an atomically detailed model of pore dendrimer interactions. We discover and explain that electrophoretic migration of polycationic PAMAM dendrimers into confined space is not dictated by the diameter of the branched molecules but by their size and generation-dependent compressibility. Differences in structural flexibility also rationalize the apparent anomaly that the experimental nanopore current read-out depends in nonlinear fashion on dendrimer size. Nanoscale confinement is inferred to reduce the protonation of the polycationic structures. Our model can likely be expanded to other dendrimers and be applied to improve the analysis of biophysical experiments, rationally design functional materials such as nanoporous filtration devices or nanoscale drug carriers that effectively pass biological pores.

show abstract

Structural Molecular Dynamics Studies on Polyamidoamine Dendrimers for a Therapeutic Application: Effects of pH and Generation

Cited by 276 publications

References 30 publications

Dynamics and Thermodynamics of Water in PAMAM Dendrimers at Subnanosecond Time Scales

Dynamics and Thermodynamics of Water in PAMAM Dendrimers at Subnanosecond Time Scales

Association of a Weakly Acidic Anti-Inflammatory Drug (Ibuprofen) with a Poly(Amidoamine) Dendrimer as Studied by Molecular Dynamics Simulations

Dendrimers in Nanoscale Confinement: The Interplay between Conformational Change and Nanopore Entrance

Contact Info

Product

Resources

About