Hwankyu Lee

Dankook University, Eidō, North Chungcheong, South Korea

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Publications (26)116.03 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Lipid bilayers, which consist of dipalmitoylglycerophosphocholines (DPPCs), PEGylated lipids, cholesterols, and elastin-like polypeptides (ELPs; [VPGVG]3) at different molar ratios, were simulated. Simulations were carried out for 2 μs using the coarse-grained (CG) model that had captured the experimentally observed phase behavior of PEGylated lipids and lateral diffusivity of DPPC bilayers. Starting with the initial position of ELPs on the bilayer surface, ELPs insert into the hydrophobic region of the bilayer because of their interaction with lipid tails, consistent with previous all-atom simulations. Lateral diffusion coefficients of DPPCs significantly increase in the bilayer composed of more ELPs and less cholesterols, showing their opposite effects on the bilayer dynamics. In particular, ELPs modulate the dynamics and phase for the disordered liquid bilayer, but not for the ordered gel bilayer, indicating that ELPs can destabilize only the disordered bilayer. In the ordered bilayer, ELP chains tend to have a spherical shape and slowly diffuse, while they are extended and diffuse faster in the disordered bilayer, indicating the effect of the bilayer phase on the conformation and diffusivity of ELPs. These findings explain the experimental observation that the ELP-conjugated liposomes are stable at 310 K (ordered phase) but become unstable and release the encapsulated drugs at 315 K (disordered phase), which suggests the effects of ELPs and cholesterols. Since the cholesterol-stabilized bilayer can be destabilized by the extended shaped ELPs only in the disordered phase (not in the ordered phase), the inclusion of cholesterols is required to safely shield drugs at 310 K as well as allow ELPs to disrupt lipids and destabilize the liposomes at 315 K.
    Physical Chemistry Chemical Physics 01/2014; · 3.83 Impact Factor
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    ABSTRACT: One application of nanotechnology in medicine that is presently being developed involves a drug delivery system (DDS) employing nanoparticles to deliver drugs to diseased sites in the body avoiding damage of healthy tissue. Recently, the mild hyperthermia-triggered drug delivery combined with anticancer agent-loaded thermosensitive liposomes was widely investigated. In this study, thermosensitive liposomes (TSLs), composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG), cholesterol, and a fatty acid conjugated elastin-like polypeptide (ELP), were developed and optimized for triggered drug release, controlled by external heat stimuli. We introduced modified ELP, tunable for various biomedical purposes, to our thermosensitive liposome (e-TSL) to convey a high thermoresponsive property. We modulated thermosensitivity and stability by varying the ratios of e-TSL components, such as phospholipid, ELP, and cholesterol. Experimental data obtained in this study corresponded to results from a simulation study that demonstrated, through the calculation of the lateral diffusion coefficient, increased permeation of the lipid bilayer with higher ELP concentrations, and decreased permeation in the presence of cholesterol. Finally, we identified effective drug accumulation in tumor tissues and antitumor efficacy with our optimized e-TSL, while adjusting lag-times for systemic accumulation.
    PLoS ONE 01/2014; 9(7):e103116. · 3.53 Impact Factor
  • Hwankyu Lee
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    ABSTRACT: Single-walled carbon nanotubes (SWNTs) covalently or noncovalently modified with polyethylene glycol (PEG) of different sizes (Mw = 550, 2000, 5000, and 7000) and grafting densities (5–16 PEGs per SWNT) were simulated using coarse-grained force fields. The covalently grafted PEGs are evenly distributed on SWNTs, while the noncovalently PEGylated SWNTs show the random distribution of PEGylated lipids adsorbed to the SWNT, in which the SWNT sidewall is less completely wrapped by PEGs and thus largely exposed to water, as was observed in experiments. For covalently PEGylated SWNTs, longer PEG chains with higher grafting density yield a larger size, more isotropic shape, and lower diffusivity of the SWNT–PEG complex. In particular, at low grafting density, the thickness of the PEG layer on SWNTs nearly equals the size of the mushroom, where the end-to-end distance of PEGs is smaller than the distance between the grafting points, similar to the conformation of an isolated chain in water. However, at high grafting density, the thickness of the PEG layer increases beyond the mushroom regime, indicating a mushroom-to-brush transition, in agreement with the Alexander–de Gennes theory. These findings indicate that the PEGylation method influences the distribution of PEG chains on SWNTs and that the PEG size and grafting density modulate the conformation of the conjugated PEG chains, which helps explain the experimentally proposed transition of the PEG conformation between mushroom and brush.
    The Journal of Physical Chemistry C. 11/2013; 117(49):26334–26341.
  • Eol Han, Hwankyu Lee
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    ABSTRACT: Bax-α5 and Bcl-xL-α5, which are shorter versions of apoptosis-regulating proteins Bax and Bcl-xL, were simulated with lipid bilayers composed of pure dioleoylglycerophosphocholine (DOPC) lipids or a mixture of DOPCs and cholesterols. Starting with the initial peptide position near the bilayer surface, both Bax-α5 and Bcl-xL-α5 bind to the bilayer because of their charge interactions with lipid head groups. After binding to the bilayer surface, Bax-α5 inserts into the pure DOPC bilayer, but not into the DOPC-cholesterol bilayer, showing the effect of cholesterols on the peptide-bilayer interaction. Despite the similar peptide structure, Bcl-xL-α5 does not insert into the bilayer, in contrast to the interaction of Bax-α5 with the bilayer. Bcl-xL-α5 predominantly has the random-coil structure in both aqueous and membrane environments, while Bax-α5 shows a higher extent of α-helical structure in the bilayer than in water, in quantitative agreement with experiment. In particular, although Bax-α5 and Bcl-xL-α5 have the same extent of the electrostatic interaction with lipid head groups, Bax-α5 has stronger hydrophobic interaction with lipid tails than does Bcl-xL-α5. These indicate that Bax-α5 retains α-helical structure, where hydrophobic residues on one side of the α-helix interact with lipid tails and thus can easily attract the peptide into the lipid-tail region, while Bcl-xL-α5 forms a random coil that tends to spread on the bilayer surface and thus has weaker hydrophobic interaction with lipid tails. Our findings help explain the experimental observation that showed that Bax-α5 disorders lipids and induces pore formation, but Bcl-xL-α5 does not.
    Physical Chemistry Chemical Physics 11/2013; · 3.83 Impact Factor
  • Eol Han, Hwankyu Lee
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    ABSTRACT: Polyethylene glycol (PEG)-grafted magainin 2 and tachyplesin I were simulated with lipid bilayers. In the simulations of PEGylated magainin 2 and tachyplesin I in water, both peptides are wrapped by PEG chains. The α-helical structure of PEGylated magainin 2 is broken in water, while β-sheet of PEGylated tachyplesin I keeps stable, similar to the structural behavior of unPEGylated peptides, in agreement with experiments. Simulations of PEGylated peptides with lipid bilayers show that PEG chains block the electrostatic interaction between cationic residues of peptides and anionic phosphates of lipids, leading to the less binding of the peptide to the bilayer surface, which is observed more significantly for magainin 2 than for tachyplesin I. Since the random-coiled magainin 2 can be more completely covered by PEGs than does the β-sheet tachyplesin I, the PEGylation effect on the decreased binding is larger for magainin 2, showing the dependence of PEGylation on the peptide structure. These simulation findings qualitatively support the experimental observation of the different extents of the reduced membrane-permeabilizing activity for PEGylated magainin 2 and tachyplesin I.
    Langmuir 10/2013; · 4.38 Impact Factor
  • Hwankyu Lee
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    ABSTRACT: We performed coarse-grained (CG) molecular dynamics (MD) simulations of single-walled carbon nanotubes (SWNTs) with lipid bilayers to understand the effect of the SWNT diameter, length, and concentration on membrane curvature and penetration. Starting with different orientations of multiple SWNTs near lipid bilayers, simulations show that SWNTs insert into the bilayer and induce membrane curvature, which is much larger than that observed from previous simulations of a single SWNT. Longer and thicker SWNTs at higher concentration cause larger membrane curvature, indicating the effect of the SWNT size and concentration, in qualitative agreement with experiments. In particular, thicker SWNTs significantly increase the bilayer height and the difference of the projected and contour bilayer areas, decrease the area compressibility, and disorder lipids. When inserted into the bilayer, thinner SWNTs mainly contact the entire tails of lipids, while thicker SWNTs are wrapped mainly by the ending tail-carbons, leading to the larger membrane curvature. This indicates the effect of SWNT diameter on the SWNT-lipid interaction, yielding different extents of membrane curvature. These findings imply that the SWNT-induced membrane penetration and curvature are modulated by a combination of SWNT length, diameter, and concentration.
    Physical Chemistry Chemical Physics 09/2013; · 3.83 Impact Factor
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    ABSTRACT: 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 9 Arg residues are more easily decomplexed by heparin than are those with 9 Arg residues. At these mole ratios, peptides longer than 9 Arg residues have cationic/anionic charge ratios in excess of unity, and produce more weakly bound complexes than 9-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 9 residues, which at mole ratio 5:1 yield a peptide/siRNA charge ratio in excess of unity, include many non-interacting 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.
    The Journal of Physical Chemistry B 05/2013; · 3.61 Impact Factor
  • Hwankyu Lee
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    ABSTRACT: Single-walled carbon nanotubes (SWNTs) wrapped with different types of lipids and polyethylene glycol (PEG)-grafted lipids were simulated with lipid bilayers. Simulations were carried out with the previously parametrized coarse-grained (CG) SWNT and PEG force fields that had captured the experimentally observed conformations of self-assembled SWNT-lipid complexes and phase behavior of PEG-grafted lipids. Simulations of multiple copies of the SWNT in water show that all pure SWNTs aggregate, lipid-wrapped SWNTs partially aggregate, but those wrapped with lipids grafted to PEG (Mw=550) completely disperse, indicating the effect of short PEG chains on interparticle aggregation, in agreement with experiment. Starting with initial SWNT orientation parallel to the bilayer surface, SWNTs wrapped with lysophospholipids and PEG(Mw=550)-grafted lipids insert into the hydrophobic region of the bilayer, while SWNTs wrapped with phospholipids and longer PEG(Mw=2000)-grafted lipids do not. These indicate that SWNTs insert because of the hydrophobic interaction with the bilayer tails, but the tight wrapping of charged lipid headgroups and long hydrophilic PEG chains can weaken the hydrophobic interaction and inhibit SWNT insertion. The inserted SWNT contact the entire tails of neighboring lipids in one leaflet of the bilayer, which disorders the lipid bilayer and induces positive curvature. Our findings indicate that interparticle aggregation, SWNT penetration, and membrane curvature can be modulated by the SWNT-lipid structure and the PEG length.
    The Journal of Physical Chemistry B 12/2012; · 3.61 Impact Factor
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    ABSTRACT: We performed all-atom and coarse-grained (CG) molecular dynamics (MD) simulations of lipid bilayers grafted with elastin-like polypeptides (ELPs; [VPGVG]n). 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.
    Macromolecules 09/2012; 45(17):7304-7312. · 5.93 Impact Factor
  • Hwankyu Lee, Hyungsu Kim
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    ABSTRACT: Self-assemblies of mixtures of a single-walled carbon nanotube (SWNT) and lipids were simulated using coarse-grained (CG) force fields previously developed and parametrized in this work. For lipids, lysophospholipids (single tail) and phospholipids (double tails) are ungrafted or grafted with poly(ethylene glycol) (PEG) at different sizes. In all simulated systems, lipids self-assemble along the SWNT, but their final conformations significantly differ. Simulations show that lysophospholipids helically wrap the SWNT as the “half-cylinder” conformation, which have been proposed by experiments but not captured by previous simulations. Phospholipids show “cylindrical micelles”, indicating the effect of the number of tails on the assembled structure. For both lysophospholipids and phospholipids, PEGylated lipids induce either “hemimicelle” or “random-adsorption” conformation, indicating dependence on the size of the lipid headgroup, because PEG chains with mushroom (solution-like) state induce the lipid-layer curvature and make lipids away from their neighbors. The number of lipids adsorbed onto SWNT increases stepwise as functions of time, implying that lipids self-assemble to their own aggregate in water modulated by the lipid headgroup and tail structure, and then the assembled lipids adsorb onto the SWNT surface. These results suggest important possible effects of PEGylation and lipid types on the self-assembled structure and mechanism, which compare favorably with experimental findings but also need to be further confirmed.
    The Journal of Physical Chemistry C. 04/2012; 116(16):9327–9333.
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    ABSTRACT: 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 (pKa 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.
    Macromolecules 11/2011; 44(21):8681-8686. · 5.93 Impact Factor
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    Hwankyu Lee, Richard W Pastor
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    ABSTRACT: Self-assembly of polyethylene glycol (PEG)-grafted lipids at different sizes and concentrations was simulated using the MARTINI coarse-grained (CG) force field. The interactions between CG PEG and CG dipalmitoylglycerophosphocholine (DPPC)-lipids were parametrized by matching densities of 19-mers of PEG and polyethylene oxide (PEO) grafted to the bilayer from all-atom simulations. Mixtures of lipids and PEG-grafted (M(w) = 550, 1250, and 2000) lipids in water self-assembled to liposomes, bicelles, and micelles at different ratios of lipids and PEGylated lipids. Average aggregate sizes decrease with increasing PEGylated-lipid concentration, in qualitative agreement with experiment. PEGylated lipids concentrate at the rims of bicelles, rather than at the planar surfaces; this also agrees with experiment, though the degree of segregation is less than that assumed in previous modeling of the experimental data. Charged lipids without PEG evenly distribute at the rim and planar surfaces of the bicelle. The average end-to-end distances of the PEG on the PEGylated lipids are comparable in liposomes, bicelles (edge or planar surface), and micelles and only slightly larger than for an isolated PEG in solution. The ability of PEGylated lipids to induce the membrane curvature by the bulky headgroup with larger PEG, and thereby modulate the phase behavior and size of lipid assemblies, arises from their relative concentration.
    The Journal of Physical Chemistry B 06/2011; 115(24):7830-7. · 3.61 Impact Factor
  • Hwankyu Lee, Ronald G. Larson
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    ABSTRACT: G4 PAMAM dendrimers grafted with poly(ethylene glycol) (PEG) of different sizes (Mw = 550 and 5000) and grafting densities (12−94% of surface terminals) were simulated using the coarse-grained (CG) force fields previously developed and reparametrized in this work. Simulations are carried out for G4, G5, and G7 un-PEGylated dendrimers that are either unprotonated, terminally protonated, or protonated on both terminals and interior sites, corresponding to pH values of >10, 7, and <5, respectively. As protonation increases, simulations show only a small (6% for G4 and G5) change of dendrimer radius of gyration Rg and show a structural transition from dense-core to dense-shell structure, both of which are in agreement with recent scattering experiments and all-atom simulations. For the PEGylated dendrimers, the Rg of the fully PEG(Mw = 5000)-grafted dendrimer also agrees well with experiment. Longer PEG chains with higher grafting density yield PEG−PEG crowding, which stretches dendrimer terminals toward water more strongly, leading to larger size and a dense-shell structure of the dendrimer. Long PEG chains at high grafting densities also penetrate into the dendrimer core, while short ones do not, which might help explain the reduced encapsulation of hydrophobic compounds seen experimentally in dendrimers that are 75%-grafted with long PEG’s (Mw = 5000). This reduced encapsulation for dendrimers with long grafted PEG’s has previously been attributed to PEG-induced dendrimer aggregation, but this explanation is not consistent with our previous simulations which showed no aggregation even with long PEG’s but is consistent with the new simulations reported here that show PEG penetration into the core of the dendrimer to which the PEG is attached.
    Macromolecules. 03/2011;
  • Hwankyu Lee, Ronald G. Larson
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    ABSTRACT: We performed molecular dynamics (MD) simu-lations of 36 copies of unmodified (charged), acetylated, and polyethylene glycol (PEG)-conjugated G4 dendrimers in dimyristoylphosphatidylcholine (DMPC) bilayers with explicit water using coarse-grained (CG) lipid and PEG force fields (FF). Attachment of small PEG chains to the dendrimer leads to the same reduction in membrane permeability as does attachment of acetyl groups, while a larger PEG size or a higher degree of PEGylation induces even fewer pores. This indicates that PEGylation is more efficient than acetylation in reducing membrane permeability and cytotoxicity, in qualitative agreement with experimental findings (Kim et al. Bioconjugate Chem. 2008, 19, 1660). Attachment of larger PEG chains makes the dendrimer−PEG complex larger and more spherical. Although a larger size and a more spherical shape are usually conducive to pore formation, a thick PEG layer on the dendrimer surface blocks the charge interaction between cationic dendrimer terminals and anionic lipid phosphate groups, and thus inhibits pore formation, despite the increased dendrimer size. Large PEG chains also keep the dendrimer−PEG complexes far from each other, suppressing interparticle aggregation.
    The Journal of Physical Chemistry C. 03/2011; 115(13).
  • Hwankyu Lee, Richard W. Pastor
    Biophysical Journal 01/2010; 98(3). · 3.67 Impact Factor
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    ABSTRACT: A coarse-grained (CG) model for polyethylene oxide (PEO) and polyethylene glycol (PEG) developed within the framework of the MARTINI CG force field (FF) using the distributions of bonds, angles, and dihedrals from the CHARMM all-atom FF is presented. Densities of neat low molecular weight PEO agree with experiment, and the radius of gyration R(g) = 19.1 A +/- 0.7 for 76-mers of PEO (M(w) approximately 3400), in excellent agreement with neutron scattering results for an equal sized PEG. Simulations of 9, 18, 27, 36, 44, 67, 76, 90, 112, 135, and 158-mers of the CG PEO (442 < M(w) < 6998) at low concentration in water show the experimentally observed transition from ideal chain to real chain behavior at 1600 < M(w) < 2000, in excellent agreement with the dependence of experimentally observed hydrodynamic radii of PEG. Hydrodynamic radii of PEO calculated from diffusion coefficients of the higher M(w) PEO also agree well with experiment. R(g) calculated from both all-atom and CG simulations of PEO76 at 21 and 148 mg/cm(3) are found to be nearly equal. This lack of concentration dependence implies that apparent R(g) from scattering experiments at high concentration should not be taken to be the chain dimension. Simulations of PEO grafted to a nonadsorbing surface yield a mushroom to brush transition that is well described by the Alexander-de Gennes formalism.
    The Journal of Physical Chemistry B 09/2009; 113(40):13186-94. · 3.61 Impact Factor
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    Hwankyu Lee, Ronald G Larson
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    ABSTRACT: We performed molecular dynamics (MD) simulations of one or two copies of polyethylene glycol of molecular weight 550 (PEG550) and 5000 (PEG5000) daltons, conjugated to generation 3 (G3) to 5 (G5) polyamidoamine (PAMAM) dendrimers with explicit water using a coarse-grained model. We found the radii of gyration of these dendrimer-PEG molecules to be close to those measured in experiments by Hedden and Bauer (Hedden , R. C. ; Bauer , B. J. Macromolecules 2003 , 36 , 1829.). Densely grafted PEG ligands (>50% of the dendrimer surface) extend like brushes, with layer thickness in agreement with theory for starlike polymers. Two dendrimer-PEG complexes in the box drift away from each other, indicating that no aggregation is induced by either short or long PEG chains, conflicting with a recent view that the cytotoxicity of some PEGylated particles might be due to particle aggregation for long PEG lengths.
    The Journal of Physical Chemistry B 09/2009; 113(40):13202-7. · 3.61 Impact Factor
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    Hwankyu Lee, Ronald G Larson
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    ABSTRACT: Recent advances in molecular dynamics simulation methodologies and computational power have allowed accurate predictions of dendrimer size, shape, and interactions with bilayers and polyelectrolytes with modest computational effort. Atomistic and coarse-grained (CG) models show strong interactions of cationic dendrimers with lipid bilayers. The CG simulations with explicit lipid and water capture bilayer penetration and pore formation, showing that pore formation is enhanced at high dendrimer concentration, but suppressed at low temperature and high salt concentration, in agreement with experiments. Cationic linear polymers have also been simulated, but do not perforate membranes, evidently because by deforming into a pancake, the charges on a linear polymer achieve intimate contact with a single bilayer leaflet. The relatively rigid dendrimers, on the other hand, penetrate the bilayer, because only by interacting with both leaflets can they achieve a similar degree of contact between charged groups. Also, a "dendrimer-filled vesicle" structure for the dendrimer-membrane interaction is predicted by mesoscale thermodynamic simulations, in agreement with a picture derived from experimental observations. In simulations of complexes of dendrimer and polyelectrolyte, anionic linear chains wrap around the cationic dendrimer and penetrate inside it. Overall, these new results indicate that simulations can now provide predictions in excellent agreement with experimental observations, and provide atomic-scale insights into dendrimer structure and dynamics.
    Molecules 02/2009; 14(1):423-38. · 2.43 Impact Factor
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    ABSTRACT: Bin/Amphiphysin/Rvs-homology (BAR) domains generate and sense membrane curvature by binding the negatively charged membrane to their positively charged concave surfaces. N-BAR domains contain an N-terminal extension (helix-0) predicted to form an amphipathic helix upon membrane binding. We determined the NMR structure and nano-to-picosecond dynamics of helix-0 of the human Bin1/Amphiphysin II BAR domain in sodium dodecyl sulfate and dodecylphosphocholine micelles. Molecular dynamics simulations of this 34-amino acid peptide revealed electrostatic and hydrophobic interactions with the detergent molecules that induce helical structure formation from residues 8-10 toward the C-terminus. The orientation in the micelles was experimentally confirmed by backbone amide proton exchange. The simulation and the experiment indicated that the N-terminal region is disordered, and the peptide curves to adopted the micelle shape. Deletion of helix-0 reduced tubulation of liposomes by the BAR domain, whereas the helix-0 peptide itself was fusogenic. These findings support models for membrane curving by BAR domains in which helix-0 increases the binding affinity to the membrane and enhances curvature generation.
    Biophysical Journal 11/2008; 95(9):4315-23. · 3.67 Impact Factor
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    Hwankyu Lee, Ronald G Larson
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    ABSTRACT: We performed molecular dynamics (MD) simulations of multiple copies of poly- l-lysine (PLL) and charged polyamidoamine (PAMAM) dendrimers in dimyristoylphosphatidylcholine (DMPC) bilayers with explicit water using the coarse-grained model developed by Marrink et al. ( J. Chem. Theory Comput. 2008, 4, 819 ). Membrane disruption is enhanced at higher concentrations and charge densities of both spheroidally shaped dendrimers and linear PLL polymers, in qualitatively agreement with experimental studies by Hong et al. (Bioconjugate Chem. 2006, 17, 728 ). However, larger molecular size enhances membrane disruption and pore formation only for dendrimers and not for the linear PLL. Despite more intimate electrostatic interactions of linear molecules than are possible for spheroidal dendrimers, only the dendrimers were found to perforate membranes, apparently because they cannot spread onto a single leaflet, and so must penetrate the bilayer to get favorable electrostatic interactions with head groups on the opposite leaflet. These results indicate that a relatively rigid spheroidal shape is more efficient than a flexible linear shape in increasing membrane permeability. These results compare favorably with experimental findings.
    The Journal of Physical Chemistry B 10/2008; 112(39):12279-85. · 3.61 Impact Factor

Publication Stats

546 Citations
116.03 Total Impact Points

Institutions

  • 2011–2014
    • Dankook University
      • Department of Chemical Engineering
      Eidō, North Chungcheong, South Korea
  • 2008–2009
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 2006
    • University of Michigan
      • Department of Biomedical Engineering
      Ann Arbor, MI, United States