Role of Solvent and Dendritic Architecture on the Redox Core

Jun 14, 2012 - Luís C. S. Filipe , Miguel Machuqueiro , Tamis Darbre , and António M. Baptista. Macromolecules 2013 46 (23), 9427-9436. Abstract | F...
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Role of Solvent and Dendritic Architecture on the Redox Core Encapsulation Rakhee C. Pani and Yaroslava G. Yingling* Department of Materials Science and Engineering, North Carolina State University, 911 Partners Way, Raleigh, North Carolina 27695, United States S Supporting Information *

ABSTRACT: Dendrimers with redox cores can accept, donate, and/or store electrons and are used in nanoscale devices like artificial receptors, magnetic resonance imaging, sensors, light harvesting antennae, and electrical switches. However, the dendrimer molecular architectures can significantly alter the encapsulation of the redox core and charge transfer pathways, thereby changing the electron transfer rates. In this study, we used molecular dynamics simulations to investigate the role of solvent and peripheral groups on molecular structure and core encapsulation of iron−sulfur G2benzyl ether dendrimers in polar and nonpolar solvent. We found that the dendrimer branches collapse in water and swell in chloroform. The presence of the long hydrophobic alkyl groups at the periphery deters the encapsulation of the core in water which may cause an increase in electron transfer rate. However, in chloroform, the dendrimer branches remain in the extended form, which leads to an increased radius of gyration. Our results suggest that peripheral alkyl chains in dendrimers cause steric hindrance, which prevents branches from back folding in chloroform solvent, but in water it reverses the trend. Overall, the presence of a hydrophobic interior and hydrophilic periphery in a dendrimer improves core encapsulation in water while hindering encapsulation in chloroform.

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INTRODUCTION Dendrimers are three-dimensional, highly branched, monodisperse molecular structures with successive layers of branched repeat units surrounding a central core. The structure and chemical properties of dendrimer core, the branch repeat units, and peripheral group define their unique functional properties. Moreover, catalytically active metal sites can be located on the periphery, branch points, or core of dendrimers, which enables their use in photophysical, catalytic, and electrochemical applications. Specifically, dendrimers with a redox core can accept, donate, and/or store electrons and are used in nanoscale devices like artificial receptors, magnetic resonance imaging, sensors, light harvesting antennae, and electrical switches.1−4 The globular conformation and compartmentalized architecture of these dendrimers can also be used to mimic globular proteins for studying electron transfers processes within biological systems.5−7 However, the molecular architectures adopted by the dendritic shell significantly affect encapsulation of the redox core alter charge transfer pathways, thereby changing the electron transfer rates.8 Dendrimers can be responsive to the microenvironment created by the dendritic shell and solvent. For example, investigation of higher generation Frechet type dendrimers with p-nitroaniline solvatochromic probes at a focal point have been shown to produce the microenvironment of nonpolar solvents.9 Another study demonstrates the use of an insulating dendritic shell with iron porphyrin core to control the redox potential © 2012 American Chemical Society

and produce a similar effect as in the presence of organic solvent.10 Long-term energy storage applications require the presence of dendritic shell around its core that may be formed by using higher generation dendrimers.11 However, wrapping of peripheral groups around a core in higher generation dendrimers often results in short donor−acceptor distances.12−16 Attenuation in electron transfer rates by utilizing higher generation dendrimers have also been extensively discussed.11,13,17 Folding of peripheral groups increases the steric bulk of dendritic ligands at the core and attenuates the electron transfer rate; this phenomenon had been seen in a palladium nanoparticle cored dendrimer18 and dendrimers with metal cores of iron sulfur,19 zincporphyrin, zinc pthalocyanines,20,21 ruthenium pyridyl complexes,22 and rhenium selenide.23 Essentially, dendrimers with radially extended branches demonstrate better redox potentials due to an increase in the planarity of their dendritic ligands. Consequently, enhanced solvent accessibility to the core will influence the redox potential of the electroactive core dendrimer.24−27 For example, the redox shifts in dendrimers with an iron−sulfur core and poly(benzyl ether) dendrons,8,28 ruthenium dendrimers with carbazole chromophores,29 polyacetylene dendrons, and Received: May 2, 2012 Revised: June 12, 2012 Published: June 14, 2012 7593

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Figure 1. Schematic representation of benzyl ether branches used in simulations with different terminal groups for (a) D1, (b) D2, (c) D3 dendrimers, (d) Fe4S4 core, and (e) initial 3D structure of a dendrimer.

carboxylate terminated thioldendrons30−32 were found to be very sensitive to the influence of solvents and solvent polarities. Dramatic shifts in the thermodynamic redox potentials of electroactive dendrimers may also arise from structural factors such as the rigidity of dendritic ligands, substitution of aromatic ligands, core position relative to the dendrimer matrix, chemical nature of the ligands, use of higher generation dendritic structures, and branch proximity with the core due to hydrogen bond formation.14,24 Thus, there is a clear relationship between these factors, solvent properties, and the dendritic shell’s microenvironment. However, the role played by energetic transitions during core encapsulation and influence of structural factors on the solvent accessibility to the core is not yet fully elucidated. In this work, we investigate the effect of branch peripheral groups and solvent polarity on the dendrimer structure using atomistic molecular dynamics (MD) simulations. Previous MD simulations have shown a detailed molecular view on the conformational changes of dendrimers associated with pH,33−35 binding to various drugs36 or DNA,37 and interactions with lipid bilayers38−40 and changes at the water/air interface.41 MD simulations were used to study how the solvent accessibility to the dendrimer changes with hydrogen bonding among the dendritic branches42 in poly(amido amine) dendrimers. Brownian dynamics and MD simulation have been used to study the density and location of peripheral groups.43,44 Here, we use Generation 2(G2) Frechet type poly(benzyl ether) dendron as a model system with a water-soluble iron−sulfur core and either hydrophilic carboxyl groups or lipophilic, longchain alkyl groups in solvents of different polarities (water or chloroform). These dendrimers possess a wide range of photochemical, electrochemical, or catalytic properties45 and are largely used either as dendritic sensors or as light harvesting antennae. Prior investigations of dendritic porphyrins,46,47 Ru(II)−tris(bipyridine) dendrimers,48,49 lanthanide core poly(benzyl ether) dendrimers,50 and redox active iron sulfur core dendrimers51,52 show a morphological and microenvironment dependence near the electro active/photoactive group on the energy transduction process or photo physical properties. We employ MD simulations to provide atomistic details of the structure of the dendrimer as a result of chemical interactions with the solvent and accessibility of the electroactive core; these atomistic interactions may lead to greater understanding of the quantitative and thermodynamic aspects of their structural

characteristics in different solvents. Our goal is to understand how steric interactions among the peripheral groups control dendrimer structure and solvent accessibility to the redox core.

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METHODS The chemical structures consist of peripheral groups like hydrophilic −COOH (in the further text referred as D1), alternating −COOH and −[(CH2)9CH3] (dendrimer D2), and lipophilic -[(CH2)9CH3 ] (dendrimer D3), as shown in Figure 1. Each subunit of the dendrimer was first geometry optimized separately using RHF/631-G basis sets and then linked to form the dendrimer molecule. The molecular electrostatic potential was calculated for optimized structures using R. E. D. tools (restrained electrostatic potential and electrostatic potential charge derive methods).53 The GAFF force field,54 which has been parametrized specifically for organic molecules, was used to represent the branches of modified poly(benzyl ether) dendrimer branches and includes the following equation: U=

∑

k1(r − req)2 +

bonds

+

∑

k 2(Ø − feq )2

angles

∑ dihedrals

Vn (1 + cos(nØ − γ )) 2

⎡ ⎛⎛ ⎞12 ⎛ ⎞6 ⎞ qiqj ⎤⎥ σij σij ⎢ + ∑ ⎢4ϵij⎜⎜⎜ ⎟⎟ + ⎜⎜ ⎟⎟ ⎟ + ⎜ r ϵrij ⎥⎥ ⎝ rij ⎠ ⎟⎠ nonbonded ⎢ ⎦ ⎣ ⎝⎝ ij ⎠

(1)

where req and Øeq are equilibration structural parameters, k1, k2, and Vn are force constants, n is the multiplicity, and γ is the phase angle for torsional angle parameters. Each dendrimer is covalently attached to an iron sulfur cluster in its reduced state [Fe4S4(SCH3)4]2− .The parameters for the iron sulfur cluster [Fe4S4(SCH3)4]2− were taken from ref 55 and are given in Tables S1 and S2 (Supporting Information). The dendrimers were solvated in a box of either explicit water (TIP3P model56) or chloroform with periodic boundaries. All MD simulations were performed using AMBER 10 software.57 Prior to the production run simulations we have subjected the solvated dendrimer to a conjugate gradient minimization cycles of 10 000 steps. The solvent was carefully equilibrated to produce an accurate modeling of solvation effects and was carried out in 11 stages58 starting from the solvent minimization for 10 000 steps while keeping the solute molecules restrained for 200 kcal/mol. 7594

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compaction of dendrimer structure in water is a result of a hydrophobic interior collapse due to increased π−π interactions between benzyl ether monomer units. Though dendrimers collapsed in water, we observed the opposite in nonpolar solvents where dendrimers swelled. In chloroform, all dendrimers formed structures of outward extending branches with the redox core centered in the dendritic shell (Figure 2b). Peripheral group sizes determined the Rg of D1, D2, and D3 dendrimers, which were calculated to be 1.4, 1.8 and 2.0 nm, respectively. The hydrodynamic radii of these dendrimers (Table S3, Supporting Information) were comparable to those reported for poly(benzyl ether) dendrimers in toluene and DMF (dimethylformamide) using SANS.60 Moreover, PPI, PAMAM, and PETIM dendrimers terminated with amine or carboxyl groups were also shown to possess a high Rg and solvent access to the interior in theta solvent.61−64 Flexible dendrimers are also known to adopt a globular shape with varying degrees of anisotropy65 and are influenced by the microenvironment around the core.66,67 We calculated the asphericity ratio, δ (Figure 3), as a measure of relative shape anisotropy (Figure S1, Supporting Information) using the following equation:

Then the system was gradually heated to 300 K in 80 ps under the 200 kcal/mol constraint on solute molecules. A short NPT MD run was performed for 200 ps with the solute molecules maintained at 200 kcal/mol constraint. Another restrained minimization step follows with the restraint of 25 kcal/mol for 10 000 steps. A second NPT MD run was performed at 25 kcal/ mol restraint for 20 ps. Subsequently, four additional 1000 steps of minimization were performed before reheating the system to 300 K at constant volume within 40 ps. The production simulations were performed for 10 ns at 300 K with a 2 fs time step, which was shown to be long enough for solvent−analyte system conversion.58 The nonbonded interactions were truncated at 9 Å. The long-range electrostatic interactions were handled using the Particle Mesh Ewald algorithm.59 All analyses were performed using PTRAJ modules and in-house codes on the MD trajectory obtained from production run. Changes in the solvation and gas-phase free energy were calculated using the Molecular Mechanics Generalized Born Solvation approach (MM-GBSA). The vibrational, translational and rotational entropies of the dendrimers were determined from normal-mode analysis.

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RESULTS AND DISCUSSION Dendrimer Size and Shape. Molecular dynamics simulations were performed to investigate the difference in structure of G2 dendrimers with benzyl ether repeat units and central [Fe4S4 (SR)]−2 core cluster induced by water and chloroform solvent. Quantitative assessments of the dendrimer shape can be made from the calculations of their radii of gyration (Figure 2a) and the relative shape anisotropy ratios

δ=1−3

I12

(3)

where I1 = Ix + Iy + Iz

and

I2 = IxIy + IyIz + IxIz

Figure 3. Asphericity parameter of dendrimers as a function of different peripheral groups in water and chloroform. Snapshots are taken at 10 ns where the iron and sulfur atoms of redox core are represented by red and yellow spheres; −COOH terminal groups are represented as blue licorice; −[(CH2)9CH3] terminal groups are represented as green licorice.

Figure 2. Temporal evolution of radius of gyration in (a) water and (b) chloroform for the D1 (red), D2 (black), and D3 (green) dendrimers. Representative simulation snapshots are taken for the D1 dendrimer.

(Figure 2b). The radius of gyration, Rg, which indicates the compactness of the structure, was calculated as an ensemble average over simulation using the following equation: ⎛ ∑ m r 2 ⎞1/2 i ⎟⎟ R g = ⎜⎜ i ⎝ ∑i mi ⎠

I2

In water, dendrimers adopted a spherical shape as evident from their low asphericity ratios that ranged from 0.01 to 0.05. D1 dendrimers with hydrophilic carboxyl groups at the periphery assumed a globular shape with the lowest asphericity ratios (Figure 3). The globular shapes adopted by these dendrimers are comparable to the globular structure of proteins that have a hydrophobic interior and hydrophilic exterior in polar medium.68−70 D2 and D3 dendrimers assumed more oblong conformations with higher asphericity ratios. Generally, these dendrimers are far from spherical; back-folding of peripheral groups and microphase separation among the peripheral groups lead to formation of a layered structure as in D2 (Figure 3). These forms are mostly seen in liquid crystalline structures53,54 and may be due to dendrimer arm flexibility. The shape distortions are similar to those observed

(2)

where m is the mass of the ith atom and r is the distance of the ith atom relative to the dendrimer center of mass. In water, the branches of all three types of dendrimers tend to fold, as indicated by a temporal decrease in the Rg values. Dendrimer D1 that has branches with carboxyl peripheral groups’ folded into the most compact structure with an Rg of 1.09 nm (Figure 2a). However, changing branch peripheral groups from carboxyl to alkyl groups (D2 and D3) formed less compact structures with Rg values of 1.3 and 1.2 nm, respectively. The 7595

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Figure 4. Folding pathway of dendrimers colored by nonbonded energy for (a, b) D1, (c, d) D2 and (e, f) D3 in water and chloroform, respectively. The rmsd values were calculated relative to the initial structure (in nm). Conformations from each basin are in the Supporting Information.

by Meijer et al. on the flattened ellipsoid shapes of propylimine dendrimers in water. Low generation poly(propyl ether imine) (PETIM) dendrimers terminated with carboxylic acid groups also deviated from spherical shapes in water due to a lack of rigidity; increased rigidity in higher generation dendrimers conferred more spherical shapes.71 A similar behavior is seen in G2 dendrons used in our simulations. In chloroform, the asphericity parameter followed a reverse trend; asphericity ratios ranged from 0.03 to 0.007. These values confirmed that the dendrimers remained nearly spherical. Because of the hydrophobicity of the internal groups, we assumed that dendrimers would form a collapsed state in water. However, the presence of hydrophilic −COOH groups in periphery resulted in globular shapes; a slight increase in shape anisotropy was due to hydrophobic peripheral groups. In chloroform, the dendrimers assumed more globular shapes in the presence of lipophilic alkyl groups at periphery. Our results suggest that dendrimer shape can be controlled with the use of soluble peripheral groups with the effect being more pronounced in higher generation dendrons. Folding Pathways of the Dendrimers. To further investigate dendrimer conformations, we assessed the interplay between steric hindrance and the energy barriers that accompany solvent interactions during folding processes. Studies have shown that the dendrimer core can be shielded from surroundings via steric interactions that increase proportionately with dendrimer generations.72−74 Steric hindrance leads to decreased solvent accessibility to the core, reduced distances between the core and peripheral groups, and disruption of the π conjugated network from nonplanar achitectures.21,75 Consequently, changes in conformation attenuate the electron transfer rate from the core to the surrounding medium.76,77 To examine the two-dimensional folding energy profiles, we plotted changes in the nonbonded energy (van der Waals and electrostatic) along two structural measurements: radius of gyration (Rg) and the root-meansquare (rms) deviation from the initial extended conformation (Figure 4). The energy landscapes account for trends in nonbonded energy as the dendritic architecture becomes more and more ordered; transitions indicate barriers and kinetic traps

during conformational search.78−81 The repulsive component of nonbonded interactions defines the steric hindrance within molecules.82,83 In water, the dendrimers D1, D2, and D3 assumed various conformations during the conformational search of the global energy minimum state with significant decrease in Rg. The qualitative change in the energy map and lowest energy conformation can account for the differences between peripheral groups. Dendrimer D1 attained the most stable energy state with a large number of conformational sampling at high energy states due to the gradual folding of arms and pairing of the benzyl ether monomers. As seen from the change in Rg of dendrimers (Figure 2), dendrimer D2 folded more quickly than dendrimer D1 with a smooth transition toward the global energy minimum due to peripheral alkyl groups. Alkyl groups at the periphery, as in D3, caused sharper folding of branches with fewer conformational states (Figure 3e). In chloroform (Figure 3b−e), the conformational transitions of dendrimers are very different from those in water due to a negligible change in Rg. Dendrimer D1 with peripheral carboxyl groups undergoes a smooth energy transition. However, the presence of peripheral alkyl groups lead to a more rugged energy landscape (Figure 3d,f), which is indicative of bottlenecks and energetic traps during the folding process. The energy gap between the initial and final conformations observed in protein-folding kinetics results in a similar energy landscape.84,85 Our results suggest that peripheral alkyl chains in dendrimers causes increased steric hindrance in chloroform solvent and reduced steric effects in water. Furthermore, we quantified the change in free energy (ΔG) of dendrimers in different solvent conditions (Table S4, Supporting Information). In water, the free energy difference becomes more favorable with the presence of alkyl peripheral groups. The ΔG of dendrimer D1 is lowest at −139.46 kcal/ mol followed by dendrimer D2 at −195.94 kcal/mol and dendrimer D3 at −306.22 kcal/mol. The driving force toward the final conformation increases with reduced steric effects among the peripheral groups. In chloroform, the free energy difference was roughly the same for dendrimers D1, D2 and D3 7596

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and calculated to be −27.92 kcal/mol, −25.97 kcal/mol and −33.11 kcal/mol respectively. Theoretical predictions of electron transfer rates, such as the Marcus theory for polar solvent, established a proportional relationship between the electron transfer rate and free energy driving force.86−88 The rate of electron transfer increases with the driving force but then decreases at very large driving forces. However, the process of electron transfer cannot be examined with MD simulations. We may assume that molecular conformation changes relate to the free energy difference between the initial and final states here:

values greater than zero indicate an exposed core. In water, the value of DCOM increases rapidly as the branches collapse, whereas in chloroform, the DCOM is lower and fluctuates along the trajectory (Figure S2, Supporting Information). In water, we observed a rapid folding of dendrimer arms which exposed the core (inset in Figure 5) as DCOM increases. In chloroform, the dendrimer arms remained distended with cores located at the center of the dendrimer matrix (Figure 5b). From our observations the presence of alkyl peripheral groups only slightly improved site isolation in water. Distribution of Surface Groups and Solvent Molecules. Solvent interactions94 play a crucial role in the stability, conformation, and shielding of the dendrimer cores. Solvent access to redox cores can also dictate changes in reduction potential due to steric congestion. To quantify the presence of the peripheral groups near the core due to back folding, we calculated the radial distribution of the peripheral groups for the last 1 ns (Figure S5, Supporting Information). We calculated that the percentage of solvent molecules accessing the core was about 0.28%, 0.19% to 0.12% in water for dendrimers D1, D2, and D3, respectively. In chloroform, the percentage of solvent molecules accessing the core was 0.47%, 0.35%, and 0.15% for dendrimers D1, D2, and D3, respectively. Even though dendrimer cores are more centered in chloroform, solvent interactions with dendrimer cores occur more frequently in chloroform than in water. To analyze the movement of the solvent molecules, we calculated the time correlation function of the solvent contacts with the dendrimers molecules at 0.4 and 0.7 nm from their cores and surfaces for a maximum time of 4 ns (Figure 6a−d).

ket = κν e−ΔG / RT

ketα − ΔG 0 where ket is the electron transfer rate, κ is the transmission coefficient, and ν is the frequency by which the transition state is approached. Compared to the extended state of dendrimers in chloroform, they form more compact structures in water. The degree of compactness increases with alkyl groups in periphery as in dendrimer D3. On the basis of these predictions, there might be an increase in the electron transfer rate as we add alkyl groups at the periphery of dendrimers in water. Although studies51 have shown that the presence of a hydrophobic environment around the core can lead to a decrease in electron transfer rate, our results indicate that a hydrophobic environment at the periphery may not produce the desired result upon encapsulation of the core. In chloroform, dendrimers remain in an extended state due to strong interaction between the solvent and solvophilic dendrimer arms. The free energy difference of the dendrimers in chloroform was very low, and generally extended conformations lead to higher electron transfer kinetics. Therefore, we must account for the position of the redox core and solvent dynamics to understand the encapsulation process. Position of the Redox Core. Site isolation, where encapsulation of the redox core by branches leads to an increased stability resulting in better encapsulation of the core,31,89,90 is important for achieving optimal functions21,91 and may improve the charge storage capabilities of dendrimers.92,93 As an indirect measure of the site isolation, we correlated the distance between the center of masses of the dendrimer branches and the iron−sulfur cores (DCOM) versus Rg (Figure 5). The value of DCOM is indicative of the relative exposure of the core and is zero where the core is fully isolated;

Figure 6. Time correlation function of (a) water and (b) chloroform contacts with the dendrimer surface and (c) water and (d) chloroform contacts with the iron sulfur cluster at 0.4 and 0.7 nm. Each figure compares the change in relaxation time as a function of surface groups.

The relaxation component indicates the solvent residence time and distinguishes between confined and flowing solvent molecules. The difference in relaxation time between the solvent molecules at the interior and surface of dendrimer molecule can also be used to quantify the solvent movement. In water, there were significant changes in the solvent relaxation component accompanied by an increase in residence time from 1 to 4 ns as when moving from the redox cores toward the dendrimer surface (Figure 6a,c). These results indicate that water molecules drift away from the cores during dendrimer folding. In addition, dendrimer D1 experiences a higher shielding effect toward the redox core. In chloroform, we

Figure 5. Core solvent exposure depicted as the distance between the core center of mass and the center of mass of dendrimer branches as a function of time in (a) water and (b) chloroform. Snapshot show the graphical representation of this distance. 7597

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at North Carolina State University. We thank Prof. Christopher B. Gorman for chemical structures and helpful discussions.

observed an obvious change in the relaxation time. Similar to water, the difference in residence time of chloroform molecules at the core and surface is greater for dendrimer D1. For dendrimer D2, we observed brief residence times of solvent molecules at the surface as compared to the core; it is indicative of solvent confinement at the branch points. Again in dendrimer D3, there is a difference in relaxation time for the solvent molecules at the periphery and near the core (Figure 6d). Increases in the solvent relaxation time indicate that solvent molecules move away from the core; this behavior was typical for dendrimer D1 in water and dendrimer D3 in chloroform that lead to better core encapsulation. These results agree well with the trend in free energy differences of dendrimers in water.

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CONCLUSIONS In this paper, we used all-atom MD simulations for iron sulfur redox core G2 poly(benzyl ether) dendrimers by varying the number of hydrophilic and hydrophobic groups at the periphery. The results were analyzed for site isolation, thermodynamics, and solvent properties. We observed that the modification of peripheral groups changes the folding process and encapsulation of the redox core in dendrimers. Also, dendrimer structures were strongly influenced by solvent polarity. Our results indicate that, in water, the presence of hydrophobic long chain alkyl groups at the periphery deter core encapsulation that may enhance the electron transfer rate. In particular, dendrimers with hydrophilic carboxyl groups at the periphery were found to have globular shapes and decreased solvent accessibility to the core. However, in chloroform, the dendrimer branches remained extended that lead to an increased radius of gyration and ease of chloroform interactions with the dendrimer arms. The presence of alkyl chains prevented the back folding of the dendrimer branches due to steric hindrance. Overall, the presence of a hydrophobic interior and hydrophilic periphery in a dendrimer improves core encapsulation in water but decreases it in chloroform.

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ASSOCIATED CONTENT

S Supporting Information *

Figures of dendrimer shape tensor, position of the redox iron− sulfur core, radial density profiles, energy−time convergence curves, number of solvent contacts as a function of time and dendrimer surface area as a function of hydrodynamic radius, and number of solvent contacts. Tables of partial charges, force field parameters, dendrimer model data, principal moments of inertia, aspect ratios, and asphericity parameters, and free energies and entropies. This material is available free of charge via the Internet at http://pubs.acs.org.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by National Science Foundation (CBET-0967559). The computer support was provided by the High Performance Computing (HPC) center 7598

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dx.doi.org/10.1021/jp304253g | J. Phys. Chem. A 2012, 116, 7593−7599