Molecular Dynamics Studies of the Size and Internal Structure of the PAMAM Dendrimer Grafted with Arginine and Histidine

Lee, Hwankyu,Choi, Joon Sig,Larson, Ronald G. American Chemical Society 2011 Macromolecules Vol.44 No.21

<P>G4 PAMAM dendrimers with each of the 64 termini grafted with zero to three histidine (His) residues followed by an end-grafted arginine (Arg) were simulated at two levels of protonation to mimic their electrostatic charges at pH 5 and 7. Arg is cationic at both pH values, and His is cationic only at pH 5. The simulations were carried out with a coarse-grained (CG) dendrimer force field that had previously predicted sizes and pH-dependent transitions between dense-core and dense-shell structures that were in agreement with experiments and all-atom simulations. In the work reported here, conjugation with Arg alone slightly increases the size of the dendrimer-conjugate complex at both pH 5 and 7 relative to that of the unmodified G4 dendrimer. Additional conjugation with His (p<I>K</I><SUB>a</SUB> of ∼6.0), and with Arg again at the dendrimer terminals, does not change the complex size at pH 7 (at which His is neutral) relative to that with Arg alone, but at pH 5 (at which His is cationic), the addition of His does increase dendrimer size, showing that increased charge increases dendrimer swelling. The increased size may increase the cytotoxicity of the dendrimer at pH 5. Also, His conjugation induces a dense-core structure at pH 7 but does not change the dense-shell structure already present at pH 5 in the G4 dendrimer without amino acid conjugation. This indicates that the conjugation of His residues densifies the inner cavity of the dendrimer core at pH 7, leaving less room for other agents, and thus likely to lower drug encapsulation efficiency. These simulations suggest important possible effects of peptide conjugation on cytotoxicity and encapsulation efficiency at different pH, which need to be confirmed by experiments.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/mamobx/2011/mamobx.2011.44.issue-21/ma2019396/production/images/medium/ma-2011-019396_0009.gif'></P>

Challenging Tube and Slip-Link Models: Predicting the Linear Rheology of Blends of Well-Characterized Star and Linear 1,4-Polybutadienes

Desai, Priyanka S.,Kang, Beom-Goo,Katzarova, Maria,Hall, Ryan,Huang, Qifan,Lee, Sanghoon,Shivokhin, Maksim,Chang, Taihyun,Venerus, David C.,Mays, Jimmy,Schieber, Jay D.,Larson, Ronald G. American Chemical Society 2016 Macromolecules Vol.49 No.13

<P>We compare predictions of two of the most advanced versions of the tube model, namely the 'Hierarchical model' by Wang et al. [J. Rheol. 2010, 54, 223] and the BoB (branch-on-branch) model by Das et al. [J. Rheol. 2006, SO, 207], against linear viscoelastic G' and G '' data of binary blends of nearly monodisperse 1,4-polybutadiene 4-arm star polymer of arm molar mass 24 000 g/mol with a monodisperse linear 1,4-polybutadiene of molar mass 58 000 g/mol. The star was carefully synthesized and characterized by temperature gradient interaction chromatography and by linear rheology over a wide frequency region through time temperature superposition. We found large failures of both the Hierarchical and BoB models to predict the terminal relaxation behavior of the star/linear blends, despite their success in predicting the rheology of the pure star and pure linear polymers. This failure occurred regardless of the choices made concerning constraint release, such as assuming arm retraction in 'fat' or 'skinny' tubes. Allowing for 'disentanglement relaxation' to cut off the constraint release Rouse process at long times does lead to improved predictions for our blends, but leads to much worse predictions for other star/linear blends described in the literature, especially those of Shivokhin et al. [Macromolecules 2014, 47, 2451]. In addition, our blends and those of Shivokhin et al. were also tested against a coarse-grained slip-link model, the 'clustered fixed slip-link model (CFSM)' of Schieber and co-workers [J. Rheol. 2014, 58, 723], in which several Kuhn steps are clustered together for computational efficiency. The CFSM with only two molecular-weight- and chain-architecture-independent parameters was able to give very good agreement with all experimental data for both of these sets of blends. In light of its success, the CFSM slip-link model may be used to address the constraint release issue more rigorously and potentially help develop improved tube models.</P>

Adsorption of Plasma Proteins onto PEGylated Lipid Bilayers: The Effect of PEG Size and Grafting Density

Lee, Hwankyu,Larson, Ronald G. American Chemical Society 2016 Biomacromolecules Vol.17 No.5

<P>Lipid bilayers grafted with polyethylene glycol (PEG) of different sizes (M-w = 750, 2000, and 5000) and grafting densities (1.6-25 mol % of PEGylated lipid in dipalmitoylphosphatidylcholine (DPPC) lipid molecules) were simulated with human serum albumin (HSA) using coarse grained force fields. At low enough grafting density, the PEG has a conformation similar to that of an isolated chain in water, and its Flory radius R-F is smaller than the distance between the grafting points (d), which is the so-called 'mushroom' regime. In contrast, densely grafted PEG chains (R-F > d) extend like brushes, with brush layer thickness given by the Alexander-de Gennes theory. A nearly spherical HSA added to this simulation migrates to the bilayer surface because of the charge interactions between anion residues of HSA and cationic cholines of DPPC, but this HSA-bilayer binding can be sterically suppressed by the PEG chains to an extent that depends on the PEG size and grafting density. In particular, regardless of the extent of the coverage of the PEG on the bilayer, the binding between HSAs and bilayers is suppressed by the PEG layer in a brush but not in a mushroom, indicating that the attractive force between proteins and bilayers can overcome the steric effect of the PEG layer in the mushroom state or in the transition region from mushroom to brush. This helps explain and clarify experiments that show much less adsorption of plasma proteins onto the particle or membrane surface when PEGs are in the brush rather than in the mushroom state.</P>

Shear banding in crystallizing colloidal suspensions

Laura T. Shereda,Ronald G. Larson,Michael J. Solomon 한국유변학회 2010 Korea-Australia rheology journal Vol.22 No.4

We characterize the shear bands generated in simple shear flow of a crystallizing colloidal suspension. 35volume % suspensions of poly(methyl methacrylate) colloids of diameter 0.68mm were dispersed in the viscous solvent dioctyl phthalate and subjected to plane Couette flow. The equilibrium structure of this suspension was crystalline and flow accelerated its crystallization kinetics significantly. Confocal laser scanning microscopy and particle tracking were used to characterize the height-dependent velocity profile in the gap of the shear flow. Near each of the two boundary surfaces, a region of high shear rate flow was observed. A low shear rate region was observed at the center of the gap. The differences in the shear rate within the two banded regions were a function of the both the applied shear rate and strain. The effect of strain indicated that the shear band development was a transient phenomenon. We found that the boundary between the high shear rate and low shear rate regions correlated with the location of crystalline and amorphous regions in the gap of the shear cell, as visualized by confocal microscopy. Furthermore, the different local shear rates observed in the banded regions were consistent with the different viscosities of the amorphous and crystalline suspensions. The results demonstrate that shear banded flows accompany shear-induced colloidal crystallization, and that the bands exhibit transient behavior because the crystallization process itself is strain dependent.

Effects of the Size, Shape, and Structural Transition of Thermosensitive Polypeptides on the Stability of Lipid Bilayers and Liposomes

Lee, Hwankyu,Kim, Hyun Ryoung,Larson, Ronald G.,Park, Jae Chan American Chemical Society 2012 Macromolecules Vol.45 No.17

<P>We performed all-atom and coarse-grained (CG) molecular dynamics (MD) simulations of lipid bilayers grafted with elastin-like polypeptides (ELPs; [VPGVG]<SUB><I>n</I></SUB>). All-atom simulations of a single ELP in water show that ELPs become more collapsed and folded as the temperature increases from 293 up to 353 K, in agreement with experiments. All-atom simulations of lipid bilayers composed of dipalmitoylglycerophosphocholine (DPPC), cholesterol, and fatty acids grafted with ELPs show that ELPs insert into the bilayer and significantly disorder lipids, to an extent that depends on the ELP length over the temperature range 293–323 K. In the bilayer, ELPs are mainly, but not entirely, random coil in character at temperatures between 293 and 315 K and, in contrast to the behavior in water, become increasing random coil and extended in length over the range 315–323 K, over which the bilayer is in the disordered liquid phase. The insertion of ELPs into the lipid-tail region is mediated by the interaction of hydrophobic Pro and Val residues with lipid tails, which become stronger at increased temperature, but the insertion is incomplete because of the interaction between hydrophilic backbones of Gly residues and the lipid headgroups. Longer time CG simulations of the transition from ordered gel to disordered liquid bilayer at 315 K in a liposome are able to capture cholesterol flip-flops between bilayer leaflets, leading to an increase in the number of cholesterols in the inner layer, which helps the bilayer accommodate the reduced membrane curvature resulting from the expansion of the bilayer area driven by the phase transition. Our findings indicate that lipid bilayers can be disrupted more effectively by the stronger hydrophobic interaction of the random coils of ELPs at 315–323 K than by the compact ELPs at 293–310 K, which helps explain the experimental observation that ELP-conjugated liposomes are stable at 310 K, but become unstable and release drugs at 315 K.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/mamobx/2012/mamobx.2012.45.issue-17/ma301327j/production/images/medium/ma-2012-01327j_0014.gif'></P>

Effect of Arginine-Rich Peptide Length on the Structure and Binding Strength of siRNA–Peptide Complexes

Kim, Minwoo,Kim, Hyun Ryoung,Chae, Su Young,Larson, Ronald G.,Lee, Hwankyu,Park, Jae Chan American Chemical Society 2013 The journal of physical chemistry. B, Condensed ma Vol.117 No.23

<P>Heparin decomplexation experiments, as well as all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) simulations, were performed to determine the effect of the size of arginine(Arg)-rich peptides on the structure and binding strength of the siRNA–peptide complex. At a fixed peptide/siRNA mole ratio of 5:1 or 10:1, the siRNA complexes with peptides longer than nine Arg residues are more easily decomplexed by heparin than are those with nine Arg residues. At these mole ratios, peptides longer than nine Arg residues have cationic/anionic charge ratios in excess of unity, and produce more weakly bound complexes than nine Arg residue ones do. AA simulations of mixtures of peptides with a single siRNA show formation of an electrostatically induced complex, and the longer peptides produce a larger complex, but with no significant increase in the number of Arg residues bound to the siRNA. Larger-scale CG-MD simulations show that multiple siRNAs can be linked together by peptides into a large complex, as observed in the experiments. The peptides longer than nine residues, which at mole ratio 5:1 yield a peptide/siRNA charge ratio in excess of unity, include many noninteracting Arg residues, which repel each other electrostatically. This leads to a less dense complex than for 9-residue peptides, which can explain why these longer complexes are more easily decomplexed by heparin molecules, as observed in the experiments. The key role of the charge ratio is supported by simulations that show that, at a mole ratio of 2.5 peptides per siRNA, the longer 18-residue peptide has a charge ratio of roughly unity and also shows a tight complex, just as the 9-residue peptide does at a 5:1 mole ratio, where its charge ratio is also unity.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jpcbfk/2013/jpcbfk.2013.117.issue-23/jp402868g/production/images/medium/jp-2013-02868g_0014.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jp402868g'>ACS Electronic Supporting Info</A></P>

Determining the Dilution Exponent for Entangled 1,4-Polybutadienes Using Blends of Near-Monodisperse Star with Unentangled, Low Molecular Weight Linear Polymers

Hall, Ryan,Kang, Beom-Goo,Lee, Sanghoon,Chang, Taihyun,Venerus, David C.,Hadjichristidis, Nikos,Mays, Jimmy,Larson, Ronald G. American Chemical Society 2019 Macromolecules Vol.52 No.4

<P>We determine experimentally the “dilution exponent” α for entangled polymers from the scaling of terminal crossover frequency with entanglement density from the linear rheology of three 1,4-polybutadiene star polymers that are blended with low-molecular-weight, unentangled linear 1,4-polybutadiene at various star volume fractions, ϕ<SUB><I>s</I></SUB>. Assuming that the rheology of monodisperse stars depends solely on the plateau modulus <I>G</I><SUB><I>N</I></SUB>(ϕ<SUB>s</SUB>) ∝ ϕ<SUB><I>s</I></SUB><SUP>1+α</SUP>, the number of entanglements per chain <I>M</I><SUB><I>e</I></SUB>(ϕ<SUB><I>s</I></SUB>) ∝ ϕ<SUB><I>s</I></SUB><SUP>-α</SUP>, and the tube-segment frictional Rouse time τ<SUB><I>e</I></SUB>(ϕ<SUB><I>s</I></SUB>) ∝ ϕ<SUB><I>s</I></SUB><SUP>-2α</SUP>, we show that only an α = 1 scaling superposes the <I>M</I><SUB><I>e</I></SUB>(ϕ<SUB><I>s</I></SUB>) dependence of the terminal crossover frequency ω<SUB><I>x</I>,<I>t</I></SUB> of the blends with those of pure stars, not α = 4/3. This is the first determination of α for star polymers that does not rely on any particular tube model implementation. We also show that a generalized tube model, the “Hierarchical model”, using the “Das” parameter set with α = 1 reasonably predicts the rheological data of the melts and blends featured in this paper.</P> [FIG OMISSION]</BR>