Publications by authors named "Dehai Liang"

68 Publications

Liquid-Liquid Phase Separation of Peptide/Oligonucleotide Complexes in Crowded Macromolecular Media.

J Phys Chem B 2021 01 29;125(1):49-57. Epub 2020 Dec 29.

Beijing National Laboratory for Molecular Sciences, Department of Polymer Science and Engineering and the Key Laboratory of Polymer Chemistry and Physics of the Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China.

The membraneless organelles (MLOs) and coacervates of oppositely charged polyelectrolytes are both formed by liquid-liquid phase separation. To reveal how the crowded cell interior regulates the MLOs, we chose the coacervates formed by peptide S5 and single-stranded oligonucleotide (ss-oligo) at 1:1 charge ratio and investigated the phase separation processes in polyacrylamide (PAM) and poly(ethylene oxide) (PEO) media at varying concentrations. Results show that the droplet formation unit is the neutral primary complex, instead of individual S5 or ss-oligo. Therefore, the coacervation process can be described by the classic theory of nucleation and growth. The dynamic scaling relationships show that S5/ss-oligo coacervation undergoes in sequence the heterogeneous nucleation, diffusion-limited growth, and Brownian motion coalescence with time. The inert crowders generate multiple effects, including accelerating the growth of droplets, weakening the electrostatic attraction, and slowing down or even trapping the droplets in the crowder network. The overall effect is that both the size and size distribution of the droplets decrease with increasing crowder concentration, and the effect of PEO is stronger than that of PAM. Our study provides a further step toward a deeper understanding of the kinetics of MLOs in crowded living cells.
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http://dx.doi.org/10.1021/acs.jpcb.0c09225DOI Listing
January 2021

Protocells with hierarchical structures as regulated by liquid-liquid and liquid-solid phase separations.

Chem Commun (Camb) 2020 Oct 9;56(80):12041-12044. Epub 2020 Sep 9.

Beijing National Laboratory for Molecular Sciences, MOE Key Laboratory of Polymer Chemistry and Physics, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.

The construction of a protocell with dynamic hierarchical structures via spontaneous phase separation sheds light on the mechanisms of life processes. Taking advantage of the transition from the liquid to solid phase, we built composite droplets with PLL/oligo/oligo solid particles randomly distributed inside a PLL/oligo liquid coacervate. The circulation and vacuolization under an electric field drive the particles into a fibrous structure and even clusters. A PLL/oligo/oligo solid phase can also form on the interface of the PLL/oligo coacervate, turning the droplet into a vesicular structure.
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http://dx.doi.org/10.1039/d0cc04432fDOI Listing
October 2020

Fission and Internal Fusion of Protocell with Membraneless "Organelles" Formed by Liquid-Liquid Phase Separation.

Langmuir 2020 07 3;36(27):8017-8026. Epub 2020 Jul 3.

Beijing National Laboratory for Molecular Sciences, MOE Key Laboratory of Polymer Chemistry and Physics, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

Construction of protocells with hierarchical structures and living functions is still a great challenge. Growing evidence demonstrates that the membraneless organelles, which facilitate many essential cellular processes, are formed by RNA, protein, and other biopolymers via liquid-liquid phase separation (LLPS). The formation of the protocell in the early days of Earth could follow the same principle. In this work, we develop a novel coacervate-based protocell containing membraneless subcompartments via spontaneous liquid-liquid phase separation by simply mixing single-stranded oligonucleotides (ss-oligo), quaternized dextran (Q-dextran), and poly(l-lysine) (PLL) together. The resulting biphasic droplet, with PLL/ss-oligo phase being the internal subcompartments and Q-dextran/ss-oligo phase as the surrounding medium, is capable of sequestering and partitioning biomolecules into distinct regions. When the droplet is exposed to salt or Dextranase, the surrounding Q-dextran/ss-oligo phase will be gradually dissociated, resulting in the chaotic movement and fusion of internal subcompartments. Besides, the external electric field at a lower strength can drive the biphasic droplet to undergo a deviated circulation concomitant with the fusion of localized subcompartments, while a high-strength electric field can polarize the whole droplet, resulting in the release of daughter droplets in a controllable manner. Our study highlights that liquid-liquid phase separation of biopolymers is a powerful strategy to construct hierarchically structured protocells resembling the morphology and functions of living cells and provides a step toward a better understanding of the transition mechanism from nonliving to living matter under prebiotic conditions.
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http://dx.doi.org/10.1021/acs.langmuir.0c01864DOI Listing
July 2020

PEGylated gene carriers in serum under shear flow.

Soft Matter 2020 Mar;16(9):2301-2310

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

The behaviour of drug/gene carriers in the blood stream under shear is still a puzzle. In this work, using the complexes formed by 21 bp DNA and poly(ethylene glycol)-b-poly(l-lysine) (PEG-PLL) of varying PEG lengths, we studied the dynamic behaviour of the complexes in the presence of fetal bovine serum (FBS) and under flow at different shear rates, a condition mimicking the internal physical environment of blood vessels. The PEG5k-PLL/DNA complex possesses a dense DNA/PLL core and a loose PEG5k protecting layer. The PEGylated DNA complexes exhibit multiple responses to external shear in the presence of FBS. The loose PEG5k layer is firstly disturbed at a shear rate below 30 s-1. The exposure of the charged core to the environment results in a secondary aggregation of the complex with FBS. The size of the aggregate is limited to a certain range as the shear rate increases to 50 s-1. The dense DNA/PLL core starts to withstand the shear force as the shear rate reaches 500 s-1. The reorganization of the core to accommodate more serum molecules leads to tertiary aggregation of the complexes. If PEG cannot form a valid layer around the complex, as in PEG2k-PLL/DNA, the complex forms an aggregate even without shear, and the first shear dependent region is missing. If the PEG layer is too stable around the complex, as in PEG10k-PLL/DNA, no tertiary aggregation occurs. The mechanism of shear on the behaviour of delivery particles in serum helps to design gene carriers with high efficacy.
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http://dx.doi.org/10.1039/c9sm02397fDOI Listing
March 2020

Dynamic Behavior of Complex Coacervates with Internal Lipid Vesicles under Nonequilibrium Conditions.

Langmuir 2020 02 12;36(7):1709-1717. Epub 2020 Feb 12.

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering , Peking University , Beijing 100871 , China.

During the evolution of life on earth, the emergence of lipid membrane-bounded compartments is one of the most enigmatic events. Endosymbiosis has been hypothesized as one of the solutions. In this work, using a coacervate droplet formed by single-stranded oligonucleotides (ss-oligo) and poly(l-lysine) (PLL) as the protocell model, we monitored the uptake of liposomes of different types and studied the dynamic behavior of the resulting composite droplet under the electric field. The coacervate droplet exhibits affinity for the liposomes of varying charges. However, the permeation of liposome is also controlled by electrostatic interactions. Dominated by electrostatic attraction, the positively charged liposome is retained inside the droplet as growing fibrous structures, while the negatively charged liposome is mainly coated on the droplet surface. Permeation and even distribution occur when the liposome and the droplet carry the same charges, or at least one of them is neutral. As an electric field is applied to trigger repetitive cycles of vacuolization in the ss-oligo/PLL droplet, the fibrous structure formed by the positively charged liposome is basically intact, while a new phase is generated together with uneven mass transport as the negatively charged liposome is internalized. Interestingly, the release of daughter droplets with similar components occurs on the droplet containing neutral liposomes. Our work not only provides a step toward creating protocells with hierarchical structures and biofunctions using a biogenetic material via simple mixing but also sheds light on the possible origin of the lipid structure inside a living organism.
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http://dx.doi.org/10.1021/acs.langmuir.9b03561DOI Listing
February 2020

Breaking Forbidden Transitions for Emission of Self-Trapped Excitons in Two Dimensional (FCHCHNH)CdBr Perovskite through Pb Alloying.

J Phys Chem Lett 2020 Jan 19;11(1):199-205. Epub 2019 Dec 19.

Department of Chemistry and Biochemistry , University of California , Santa Cruz , California 95064 , United States.

In this work, a new two-dimensional Cd-based (FCHCHNH)CdBr perovskite (Cd-P) with indirect bandgap and a direct Pb-based (FCHCHNH)PbBr (Pb-P) are successfully synthesized with isostructural features. Compared to the blueish white light emission of Pb-P, almost no white light can be observed for Cd-P due to the forbidden transition of self-trapped exciton (STE) emission. Interestingly, the white light emission of CdPb-P ( represents the feed ratio of Cd) is significantly improved with the photoluminescence (PL) quantum yield (QY) raising from <1% to 32.5% by alloying these two isostructural perovskites, which is attributed to the breaking of selection rules for forbidden transitions of STEs with Jahn-Teller like octahedral distortion, as suggested by the results from density functional theory (DFT) calculations and time-resolved spectroscopies. This study demonstrates the intriguing effect of alloying on activating STE emission as an effective approach to control and enhance the optical properties of metal halide perovskites.
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http://dx.doi.org/10.1021/acs.jpclett.9b03213DOI Listing
January 2020

Fluorinated Spacers Regulate the Emission and Bandgap of Two-Dimensional Single-Layered Lead Bromide Perovskites by Hydrogen Bonding.

J Phys Chem Lett 2019 Sep 27;10(17):5271-5276. Epub 2019 Aug 27.

Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province, Shantou University, Shantou, Guangdong 515063, China.

In this work, four kinds of two-dimensional single-layered F-substituted ethylammonium lead halide perovskites (LHPs, (FCHCHNH)PbBr, = 0, 1, 2, and 3) are successfully synthesized. The introduction of terminal F atoms promotes the formation of an inter- and intramolecular hydrogen bonding network, which has a great impact on the configuration of F-substituted EA, the interlayer spacing, and distortion of inorganic layers. Among these four as-prepared samples, (FCHCHNH)PbBr shows the smallest bandgap (∼2.72 eV) and best photoconductivity because of the interlayer electronic coupling. Owing to the strong coupling between excitons and lattice, intense white light emission (quantum yield: 12%) is observed for (FCHCHNH)PbBr. Benefiting from the hydrophobic nature of F-C bonds, (CFCHNH)PbBr presents a greatly improved stability toward moisture. These findings reveal that constructing inter- and intramolecular interaction can serve as an effective approach for tuning the broadband emission and the interlayer conductivity of single-layered LHPs.
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http://dx.doi.org/10.1021/acs.jpclett.9b02172DOI Listing
September 2019

Mass Transport in Coacervate-Based Protocell Coated with Fatty Acid under Nonequilibrium Conditions.

Langmuir 2019 04 12;35(16):5587-5593. Epub 2019 Apr 12.

Beijing National Laboratory for Molecular Sciences, MOE Key Laboratory of Polymer Chemistry and Physics, College of Chemistry and Molecular Engineering , Peking University , Beijing 100871 , China.

Construction of protocell models from prebiotically plausible components to mimic the basic features or functions of living cells is still a challenge. In this work, we prepare a hybrid protocell model by coating sodium oleate on the coacervate droplet constituted by poly(l-lysine) and oligonucleotide and investigate the transport of different molecules under electric field. Results show that sodium oleate forms a layered viscoelastic membrane on the droplet surface, which is selectively permeable to small, polar molecules, such as oligolysine. As the droplet is stimulated at 10 V cm, the oleate membrane slips along the direction of electric field while maintaining its integrity. Most of the molecules are still excluded under such conditions. As repetitive cycles of vacuolization occur at 20 V cm, all molecules are internalized and sequestrated in the droplet through their specific pathways except enzyme, which anchors in the oleate membrane and is immune to electric field. Cascade enzymatic reactions are then carried out, and the product generated from the membrane exhibits a time-dependent concentration gradient across the droplet. Our work makes a step toward the nonequilibrium functionalization of synthetic protocells capable of biomimetic operations.
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http://dx.doi.org/10.1021/acs.langmuir.9b00470DOI Listing
April 2019

Interaction between human serum albumin and cholesterol-grafted polyglutamate as the potential carriers of protein drugs.

Acta Pharm Sin B 2019 Jan 7;9(1):186-193. Epub 2018 Aug 7.

Key Laboratory of Advanced Materials (MOE), Department of Chemical Engineering, Tsinghua University, Beijing 100084, China.

Currently there is no successful platform technology for the sustained release of protein drugs. It seems inevitable to specifically develop new materials for such purpose, and hence the understanding of protein-material interactions is highly desirable. In this study, we synthesized cholesterol-grafted polyglutamate (PGA--Chol) as a hydrophobically-modified polypeptide, and thoroughly characterized its interaction with a model protein (human serum albumin) in the aqueous solution by using circular dichroism, fluorescence methods, and light scattering. With the protein concentration fixed at 5 μmol/L, adding PGA--Chol polymers into the solution resulted in continuous blue shift of the protein fluorescence (from 339 to 332 nm), until the polymer molar concentration reached the same value as the protein. In contrast, the un-modified polyglutamate polymers apparently neither affected the protein microenvironment nor formed aggregates. Based on the experimental data, we proposed a physical picture for such protein-polymer systems, where the polymer first bind with the protein in a 1:1 molar ratio a fraction of their hydrophobic pendant cholesterol resides along the polymer chain. In this protein/polymer complex, there are excess unbound cholesterol residues. As the polymer concentration increases, the polymers form multi-polymer aggregates around 200 nm in diameter the same hydrophobic cholesterol residues. The protein/polymer complex also participate in the aggregation their excess cholesterol residues, and consequently the proteins are encapsulated into the nanoparticles. The encapsulation was also found to increase the thermal stability of the model protein.
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http://dx.doi.org/10.1016/j.apsb.2018.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361731PMC
January 2019

Membrane-mediated transport in a non-equilibrium hybrid protocell based on coacervate droplets and a surfactant.

Chem Commun (Camb) 2018 Dec;54(98):13849-13852

Beijing National Laboratory for Molecular Sciences, MOE Key Laboratory of Polymer Chemistry and Physics, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.

A hybrid protocell is constructed to investigate the membrane transport of neutral, cationic, and anionic molecules under non-equilibrium conditions. Each model molecule follows a specific pathway to be internalized and generates different distributions in the droplets. This work provides a step towards functionalization of synthetic protocells capable of biomimetic operations.
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http://dx.doi.org/10.1039/c8cc08337aDOI Listing
December 2018

Electric field-induced circulation and vacuolization regulate enzyme reactions in coacervate-based protocells.

Soft Matter 2018 Aug 27;14(31):6514-6520. Epub 2018 Jul 27.

Beijing National Laboratory for Molecular Sciences, MOE Key Laboratory of Polymer Chemistry and Physics, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.

Artificial protocells operating under non-equilibrium conditions offer a new approach to achieve dynamic features with life-like properties. Using coacervate micro-droplets comprising polylysine (PLL) and a short single-stranded oligonucleotide (ss-oligo) as a membrane-free protocell model, we demonstrate that circulation and vacuolization can occur simultaneously inside the droplet in the presence of an electric field. The circulation is driven by electrohydrodynamics and applies specifically to the major components of the protocell (PLL and ss-oligo). Significantly, under low electric fields (E = 10 V cm) the circulation regulates the movement of the vacuoles, while high levels of vacuolization produced at higher electric fields can deform or reshape the circulation. By taking advantage of the interplay between vacuolization and circulation, we achieve dynamic localization of an enzyme cascade reaction at specific droplet locations. In addition, the spatial distribution of the enzyme reaction is globalized throughout the droplet by tuning the coupling of the circulation and vacuolization processes. Overall, our work provides a new strategy to create non-equilibrium dynamic behaviors in molecularly crowded membrane-free synthetic protocells.
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http://dx.doi.org/10.1039/c8sm01168kDOI Listing
August 2018

Inward Budding and Endocytosis of Membranes Regulated by de Novo Designed Peptides.

Langmuir 2018 05 16;34(21):6183-6193. Epub 2018 May 16.

Protein-mediated endocytosis of membrane is a key event in biological system. The mechanism, however, is still not clear. Using a de novo designed bola-type peptide KKKLLLLLLLLKKK (KLK) as a protein mimic, we studied how it induced giant unilamellar vesicle (GUV) to form inward buds or endocytosis at varying conditions. Results show that the inward budding is initiated as the charged lipids are neutralized by KLK, which results in a negative spontaneous curvature. If the charged lipids have unsaturated tails, the buddings are slim fibrils, which can further wrap into a spherical structure. In the case of saturated charged lipids, the buddings are rigid tubules, stable in the studied time period. The unsaturated lipid to saturated lipid ratio in the mother membrane is another key parameter governing the shape and dynamics of the buds. A complete endocytosis is observed when KLK is attached with a hydrophobic moiety, suggesting that hydrophobic interaction helps the buds to detach from the mother membrane. The molecules in the surrounding medium, such as negatively charged oligonucleotides, are engulfed into the GUV via endocytosis pathway induced by KLK. Our study provides a novel strategy for illustrating the endocytosis mechanism by using peptides of simple sequence.
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http://dx.doi.org/10.1021/acs.langmuir.8b00882DOI Listing
May 2018

Shear Effects on Stability of DNA Complexes in the Presence of Serum.

Biomacromolecules 2017 Oct 1;18(10):3252-3259. Epub 2017 Sep 1.

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University , Beijing, China , 100871.

The behavior of nanocarriers, even though they are well-defined at equilibrium conditions, is unpredictable in living system. Using the complexes formed by plasmid DNA (pDNA) and K (K: lysine), protamine, or polylysine (PLL) as models, we studied the dynamic behavior of gene carriers in the presence of fetal bovine serum (FBS) and under different shear rates, a condition mimicking the internal physical environment of blood vessels. Without shear, all the positively charged complexes bind to the negatively charged proteins in FBS, leading to the formation of large aggregates and even precipitates. The behaviors are quite different under shear. The shear generates two effects: a mechanical force to break down the complex into smaller size particles above a critical shear rate and a stirring effect leading to secondary aggregation of complexes below the critical shear rate. In the studied shear rate from 100 to 3000 s, the mechanical force plays a key role in K/pDNA and protamine/pDNA, while the stirring effect is dominant in PLL/pDNA. A model study shows that the interfacial tension, the chain density, and the elasticity of the complexes determine their responsiveness to shear force. This study is helpful to understand the fate of drug/gene carriers under physiological conditions. It also gains insight in designing drug/gene carriers with desirable properties for in vivo applications.
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http://dx.doi.org/10.1021/acs.biomac.7b00900DOI Listing
October 2017

Enzymatic activity inside a DNA/peptide complex.

Phys Chem Chem Phys 2017 Aug;19(33):22487-22493

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Bejing 100871, China.

The mutual interaction between enzymes and their environments plays a key role in various life processes. In this study, using the complexes formed by salmon DNA and a de novo designed peptide, Ac-RRRRRRRRRGALGLPGKGGGLQRLTALDGR-NH (abbreviated as RR-30), as a model, we studied the activity of collagenase encapsulated inside the complex. Collagenase is able to cleave RR-30 at a LG/LP site, generating two shorter length peptides, which decreases the stability of the complex. Results show that the complex dissociates with time in the presence of collagenase. The dissociation rate is linearly proportional to the collagenase concentration. On the other hand, the collagenase activity is severely deteriorated inside the complex, where only 1/3 of the enzyme is active. We attribute it to the electrostatic interaction and hydrophobic interaction between collagenase and the components of the complex. Therefore, the mutual interaction determines the structure and kinetics of the DNA/peptide complex.
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http://dx.doi.org/10.1039/c7cp04066kDOI Listing
August 2017

Effects of Structural Flexibility on the Kinetics of DNA Y-Junction Assembly and Gelation.

Langmuir 2016 12 21;32(48):12862-12868. Epub 2016 Nov 21.

Beijing National Laboratory for Molecular Sciences, Department of Polymer Science and Engineering and the Key Laboratory of Polymer Chemistry and Physics of the Ministry of Education, College of Chemistry and Molecular Engineering, Peking University , Beijing 100871, China.

The kinetics of DNA assembly is determined not only by temperature but also by the flexibility of the DNA tiles. In this work, the flexibility effect was studied with a model system of Y-junctions, which contain single-stranded thymine (T) loops in the center. It was demonstrated that the incorporation of a loop with only one thymine prominently improved the assembly rate and tuned the final structure of the assembly, whereas the incorporation of a loop of two thymines exhibited the opposite effect. These observations could be explained by the conformation adjustment rate and the intermotif binding strength. Increasing DNA concentration hindered the conformational adjustment rate of DNA strands, leading to the formation of hydrogels in which the network was connected by ribbons. Therefore, the gel can be treated as a metastable state during the phase transition.
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http://dx.doi.org/10.1021/acs.langmuir.6b03299DOI Listing
December 2016

The dispersion and aggregation of graphene oxide in aqueous media.

Nanoscale 2016 Aug 19;8(30):14587-92. Epub 2016 Jul 19.

Beijing National Laboratory for Molecular Sciences, Key Laboratory for the Physics and Chemistry of Nanodevices, State Key Laboratory of Rare Earth Materials, Chemistry and Applications, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

Graphene oxide (GO), as a typical two-dimensional material, possesses a range of oxygen-containing groups and shows surfactant and/or polyelectrolyte-like characteristics. Herein, GO sheets with narrow size distribution were prepared by an ultracentrifugation-based process and the aggregation behaviour of GO in pure water and an electrolyte aqueous solution were studied using laser light scattering (LLS). When adding common electrolytes, such as NaCl and MgCl2, into the GO dispersions, aggregation occurs and irreversible coagulation eventually occurs too. However, the GO dispersion can still remain stable when adding excess AlCl3. The zeta potential of the GO dispersion changes from negative to positive after the addition of access AlCl3, indicating that electrostatic repulsion is still responsible for the dispersion of GO, which is in good agreement with the LLS results. This finding on the dispersion of GO may be applied in the solution processing of GO. It also expands the scope of the design and preparation of new GO-based hybrid materials with different functions.
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http://dx.doi.org/10.1039/c6nr03503eDOI Listing
August 2016

Effects of chain flexibility on the properties of DNA hydrogels.

Soft Matter 2016 Jul 28;12(25):5537-41. Epub 2016 Apr 28.

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Bejing 100871, China.

The effect of chain rigidity on the mechanic properties of DNA hydrogels was studied. Counterintuitively, the hydrogel formed by mainly flexible chains exhibited better stability, stretchability, and much mechanical properties than the hydrogel containing only rigid chains. Calculations showed that the crosslinking ratio in the hydrogel formed by flexible chains was about twice that of the hydrogel formed by rigid chains under the same conditions. We attributed this to the ease of conformational adjustment of flexible chains. Incorporation of 25% rigid chains further improved the performance of DNA hydrogel by shrinking the pore size and tuning its distribution.
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http://dx.doi.org/10.1039/c6sm00283hDOI Listing
July 2016

Inter-molecular β-sheet structure facilitates lung-targeting siRNA delivery.

Sci Rep 2016 Mar 9;6:22731. Epub 2016 Mar 9.

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences; Institute of Molecular Medicine, Peking University, Beijing 100871, China.

Size-dependent passive targeting based on the characteristics of tissues is a basic mechanism of drug delivery. While the nanometer-sized particles are efficiently captured by the liver and spleen, the micron-sized particles are most likely entrapped within the lung owing to its unique capillary structure and physiological features. To exploit this property in lung-targeting siRNA delivery, we designed and studied a multi-domain peptide named K-β, which was able to form inter-molecular β-sheet structures. Results showed that K-β peptides and siRNAs formed stable complex particles of 60 nm when mixed together. A critical property of such particles was that, after being intravenously injected into mice, they further associated into loose and micron-sized aggregates, and thus effectively entrapped within the capillaries of the lung, leading to a passive accumulation and gene-silencing. The large size aggregates can dissociate or break down by the shear stress generated by blood flow, alleviating the pulmonary embolism. Besides the lung, siRNA enrichment and targeted gene silencing were also observed in the liver. This drug delivery strategy, together with the low toxicity, biodegradability, and programmability of peptide carriers, show great potentials in vivo applications.
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http://dx.doi.org/10.1038/srep22731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783658PMC
March 2016

Non-equilibrium behaviour in coacervate-based protocells under electric-field-induced excitation.

Nat Commun 2016 Feb 15;7:10658. Epub 2016 Feb 15.

Beijing National Laboratory for Molecular Sciences, MOE Key Laboratory of Polymer Chemistry and Physics, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

Although numerous strategies are now available to generate rudimentary forms of synthetic cell-like entities, minimal progress has been made in the sustained excitation of artificial protocells under non-equilibrium conditions. Here we demonstrate that the electric field energization of coacervate microdroplets comprising polylysine and short single strands of DNA generates membrane-free protocells with complex, dynamical behaviours. By confining the droplets within a microfluidic channel and applying a range of electric field strengths, we produce protocells that exhibit repetitive cycles of vacuolarization, dynamical fluctuations in size and shape, chaotic growth and fusion, spontaneous ejection and sequestration of matter, directional capture of solute molecules, and pulsed enhancement of enzyme cascade reactions. Our results highlight new opportunities for the study of non-equilibrium phenomena in synthetic protocells, provide a strategy for inducing complex behaviour in electrostatically assembled soft matter microsystems and illustrate how dynamical properties can be activated and sustained in microcompartmentalized media.
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http://dx.doi.org/10.1038/ncomms10658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756681PMC
February 2016

Effect of intra-membrane C60 fullerenes on the modulus of elasticity and the mechanical resistance of gel and fluid lipid bilayers.

Nanoscale 2015 Oct;7(40):17102-8

Oxford Martin Programme on Nanotechnology, Department of Physics, University of Oxford, Parks Road, Oxford, UK OX1 3PU.

Penetration and partition of C60 to the lipid bilayer core are both relevant to C60 toxicity, and useful to realise C60 biomedical potential. A key aspect is the effect of C60 on bilayer mechanical properties. Here, we present an experimental study on the mechanical effect of the incorporation of C60 into the hydrophobic core of fluid and gel phase zwitterionic phosphatidylcholine (PC) lipid bilayers. We demonstrate its incorporation inside the hydrophobic lipid core and the effect on the packing of the lipids and the vesicle size using a combination of infrared (IR) spectroscopy, atomic force microscopy (AFM) and laser light scattering. Using AFM we measured the Young's modulus of elasticity (E) of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) in the absence (presence) of intra-membranous C60 at 24.5 °C. E of fluid phase supported bilayers is not altered by C60, but E increases with incorporation of C60 in gel phase bilayers. The increase is higher for longer hydrocarbon chains: 1.6 times for DPPC and 2 times for DSPC. However the mechanical resistance of gel phase bilayers of curved bilayered structures decreases with the incorporation of C60. Our combined results indicate that C60 causes a decrease in gel phase lipid mobility, i.e. an increase in membrane viscosity.
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http://dx.doi.org/10.1039/c5nr04719fDOI Listing
October 2015

The growth of filaments under macromolecular confinement using scaling theory.

Chem Commun (Camb) 2015 Nov 17;51(88):15928-31. Epub 2015 Sep 17.

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China.

Quantitatively describing macromolecular confinement is still a challenge. Using the assembly of DNA tiles in a polyacrylamide network as a model, we studied the effect of macromolecular confinement on the growth of the filament by scaling theory. The results show that the confinement regulates the morphology, the initial growth rate v, and the eventual length of the filament Nm. The initial growth rate is dependent on the medium viscosity η as ν∝η(-0.94), and the filament adjusts its length in the given confined space as Nm∝ (ξ/Rg)(1.8), with ξ being the mesh size of the polyacrylamide solution and Rg being the radius of gyration of polyacrylamide.
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http://dx.doi.org/10.1039/c5cc06748kDOI Listing
November 2015

Complexation behavior of oppositely charged polyelectrolytes: Effect of charge distribution.

J Chem Phys 2015 May;142(20):204902

School of Physics and Key Laboratory of Functional Polymer Materials of Ministry of Education, Nankai University, Tianjin 300071, China.

Complexation behavior of oppositely charged polyelectrolytes in a solution is investigated using a combination of computer simulations and experiments, focusing on the influence of polyelectrolyte charge distributions along the chains on the structure of the polyelectrolyte complexes. The simulations are performed using Monte Carlo with the replica-exchange algorithm for three model systems where each system is composed of a mixture of two types of oppositely charged model polyelectrolyte chains (EGEG)5/(KGKG)5, (EEGG)5/(KKGG)5, and (EEGG)5/(KGKG)5, in a solution including explicit solvent molecules. Among the three model systems, only the charge distributions along the chains are not identical. Thermodynamic quantities are calculated as a function of temperature (or ionic strength), and the microscopic structures of complexes are examined. It is found that the three systems have different transition temperatures, and form complexes with different sizes, structures, and densities at a given temperature. Complex microscopic structures with an alternating arrangement of one monolayer of E/K monomers and one monolayer of G monomers, with one bilayer of E and K monomers and one bilayer of G monomers, and with a mixture of monolayer and bilayer of E/K monomers in a box shape and a trilayer of G monomers inside the box are obtained for the three mixture systems, respectively. The experiments are carried out for three systems where each is composed of a mixture of two types of oppositely charged peptide chains. Each peptide chain is composed of Lysine (K) and glycine (G) or glutamate (E) and G, in solution, and the chain length and amino acid sequences, and hence the charge distribution, are precisely controlled, and all of them are identical with those for the corresponding model chain. The complexation behavior and complex structures are characterized through laser light scattering and atomic force microscopy measurements. The order of the apparent weight-averaged molar mass and the order of density of complexes observed from the three experimental systems are qualitatively in agreement with those predicted from the simulations.
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http://dx.doi.org/10.1063/1.4921652DOI Listing
May 2015

Local de-condensation of double-stranded DNA in oppositely charged polyelectrolyte as induced by spermidine.

Soft Matter 2015 Jun;11(23):4705-9

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, P. R. China.

How polyamines such as spermidine cooperate with histone to condense and de-condense DNA during transcription has not been clarified. In this work, using the complex of DNA and poly(L-lysine) (PLL) at +/- ratio of 0.5 as a model of nucleosome, we monitored the de-condensation of DNA in the presence of spermidine. As revealed by the results from atomic force microscopy and time-resolved laser light scattering, spermidine was able to transform the spherical complex into a core-shelled structure, with the hard core being the DNA-PLL complex and the soft shell being DNA and spermidine. The soft shell evolved into a coiled DNA conformation with time. Such a local de-condensation process should be helpful in understanding the DNA transcription and cell division process in vivo.
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http://dx.doi.org/10.1039/c5sm00552cDOI Listing
June 2015

Axial growth and fusion of liposome regulated by macromolecular crowding and confinement.

Langmuir 2015 May 22;31(17):4822-6. Epub 2015 Apr 22.

†Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.

The endomembrane system, including the endoplasmic reticulum, Golgi apparatus, lysosomes, and endosomes, is located in the crowded intracellular environment. An understanding of the cellular structure and functions requires knowledge of how macromolecular crowding and confinement affect the activity of membrane and its proteins. Using negatively charged liposome and the peptide K3L8K3 as a model system, we studied the aggregation behavior of liposome in a matrix of polyacrylamide and hyaluronic acid. Without matrix, the liposomes form spherical aggregates in the presence of K3L8K3. However, they orient in one dimension and fuse into a tube up to 40 μm long in the matrix. The growth of the tube is via end-to-end connection. This anisotropic growth is mainly due to the macromolecular confinement provided by the polymer network. The study of the interactions between liposome and peptide in the crowded environment helps to reveal the mechanism of membrane-related processes in vivo.
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http://dx.doi.org/10.1021/la504699yDOI Listing
May 2015

Mechanism of DNA assembly as revealed by energy barriers.

Chem Commun (Camb) 2015 May;51(36):7717-20

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China.

The mechanism of DNA assembly is revealed by analyzing the energy barriers during nucleation and growth. The assembly is controlled by two competing parameters: the conformation adjustment rate of DNA strands and the spreading rate of new strands on the nuclei surface, both of which are temperature dependent and can be tuned by sequence design.
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http://dx.doi.org/10.1039/c5cc00783fDOI Listing
May 2015

Peptides containing blocks of different charge densities facilitate cell uptake of oligonucleotides.

Phys Chem Chem Phys 2015 Apr 4;17(14):8653-9. Epub 2015 Mar 4.

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China.

Polyelectrolyte complexes (PECs) are of great importance in drug delivery and gene therapy. The density and the distribution of the charges are key parameters of a polyelectrolyte, determining the structure of the complex and the kinetics of the complexation. Using peptides of precisely-controlled charge density as model molecules, we showed that the presence of weakly-charged peptides, (KGGG)5 or (KGKG)5, did not affect the complexation of highly-charged peptides (KKKK)5 with 21 bp oligonucleotides. However, peptide containing blocks of different charge densities, such as (KKKK)5-b-(KGGG)5 or (KKKK)5-b-(KGKG)5, exhibited superior performance during complexation. With a relatively uniform small size, the complex was also stable in serum. More importantly, the cellular uptake of the complex was greatly enhanced by a ratio of 40-60%, compared to that of the complex formed by uniformly-charged peptides. We attributed the improvement to the structure of the complex, in which the highly-charged blocks form the core with the oligonucleotide whilst the weakly-charged blocks dangle outside, preventing the complexes from further aggregation.
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http://dx.doi.org/10.1039/c4cp05988cDOI Listing
April 2015

Complete dissociation and reassembly behavior as studied by using poly(ethylene glycol)-block-poly(glutamate sodium) and kanamycin A.

Soft Matter 2015 Mar;11(10):1930-6

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, P.R. China.

Kanamycin A, an amino modified sugar, can interact with poly(ethylene glycol)-block-poly(glutamate sodium) (PEG114-PGlu64) via electrostatic interactions (with PGlu) and hydrogen bonding (with PEG). The interplay of these two forces determines the assembly process and the resulting structure. In deionized water, kanamycin A and PEG114-PGlu64 form a spherical structure at [+]/[-] = 3.5. This structure dissociates instantly and completely in the presence of 30 mM NaCl. However, a new structure is reassembled in about 2 hours. A similar phenomenon is observed when the buffer pH is increased from 7.8 to 8.3. We attribute the distinct dissociation/reassembly process to the reestablishment of the balance between electrostatic interactions and hydrogen bonding. The dissociation/reassembly process in response to environmental changes offers a novel approach to release the loaded cargo in a controlled manner.
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http://dx.doi.org/10.1039/c4sm02656jDOI Listing
March 2015

Dynamic assembly of DNA and polylysine mediated by electric energy.

Chem Commun (Camb) 2015 Jan;51(8):1506-9

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.

Under an electric field, the complexes formed by DNA and polylysine exhibit novel features, such as selective merging of particles, ejecting of daughter vehicles, and differentiation of particles of varying mobility. The mobility of the complex could be three times faster than that of free DNA.
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http://dx.doi.org/10.1039/c4cc07537dDOI Listing
January 2015

Relationship between peptide structure and antimicrobial activity as studied by de novo designed peptides.

Biochim Biophys Acta 2014 Dec 23;1838(12):2985-93. Epub 2014 Aug 23.

Beijing National Laboratory for Molecular Sciences and the Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871 China. Electronic address:

As fundamental components in innate immunity, antimicrobial peptides (AMPs) hold great potentials in the treatment of persistent infections involving slow-growing or dormant bacteria in which, selective inhibition of prokaryotic bacteria in the context of eukaryotic cells is not only an essential requirement, but also a critical challenge in the development of antimicrobial peptides. To identify the sequence and structural properties critical for antimicrobial activity, a series of peptides varying in sequence, length, hydrophobicity/charge ratio, and secondary structure, were designed and synthesized. Their antimicrobial activities were then tested using Escherichia coli and HEK293 cells, together with several index activities against model membrane, including liposome leakage, fusion, and aggregation. While no evident correlation between the antimicrobial activity and the property of the peptides was observed, common activities against model membrane were nevertheless identified for the active antimicrobial peptides: mediating efficient membrane leakage, negligible membrane fusion and liposome aggregation. Therefore, in addition to identifying one highly active antimicrobial peptide, our study further sheds light on the design principle for these molecules.
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http://dx.doi.org/10.1016/j.bbamem.2014.08.018DOI Listing
December 2014
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