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Protein Folding
Proofreading of Peptide-MHC Complexes through Dynamic Multivalent Interactions
Feb 23, 2017   Frontiers In Immunology
Thomas C, Tampé R
Proofreading of Peptide-MHC Complexes through Dynamic Multivalent Interactions
Feb 23, 2017
Frontiers In Immunology
The adaptive immune system is able to detect and destroy cells that are malignantly transformed or infected by intracellular pathogens. Specific immune responses against these cells are elicited by antigenic peptides that are presented on major histocompatibility complex class I (MHC I) molecules and recognized by cytotoxic T lymphocytes at the cell surface. Since these MHC I-presented peptides are generated in the cytosol by proteasomal protein degradation, they can be metaphorically described as a window providing immune cells with insights into the state of the cellular proteome. A crucial element of MHC I antigen presentation is the peptide-loading complex (PLC), a multisubunit machinery, which contains as key constituents the transporter associated with antigen processing (TAP) and the MHC I-specific chaperone tapasin (Tsn). While TAP recognizes and shuttles the cytosolic antigenic peptides into the endoplasmic reticulum (ER), Tsn samples peptides in the ER for their ability to form stable complexes with MHC I, a process called peptide proofreading or peptide editing. Through its selection of peptides that improve MHC I stability, Tsn contributes to the hierarchy of immunodominant peptide epitopes. Despite the fact that it concerns a key event in adaptive immunity, insights into the catalytic mechanism of peptide proofreading carried out by Tsn have only lately been gained
Facet-Dependent Thermal Instability in LiCoO2
Feb 23, 2017   Nano Letters
Sharifi-Asl S, Soto FA, Nie A, Yuan Y, Asayesh-Ardakani H, Foroozan T, Yurkiv V, Song B, Mashayek F, Klie RF, Amine K, Lu J, Balbuena PB, Shahbazian-Yassar R
Facet-Dependent Thermal Instability in LiCoO2
Feb 23, 2017
Nano Letters
Thermal runaways triggered by the oxygen release from oxide cathode materials pose a major safety concern for widespread application of lithium ion batteries. Utilizing in-situ aberration-corrected scanning transmission electron microscopy (STEM) and electron energy loss spectroscopy (EELS) at high temperatures, we show that oxygen release from LixCoO2 cathode crystals is occurring at the surface of particles. We correlated this local oxygen evolution from the LixCoO2 structure with local phase transitions spanning from layered to spinel and then to rock salt structure upon exposure to elevated temperatures. Ab initio molecular dynamics simulations (AIMD) results show that oxygen release is highly dependent on LixCoO2 facet orientation. While the [001] facets are stable at 300 °C, oxygen release is observed from the [012] and [104] facets, where under-coordinated oxygen atoms from the delithiated structures can combine and eventually evolve as O2. The novel understanding that emerges from the present study provides in-depth insights into the thermal runaway mechanism of Li-ion batteries and can assist the design and fabrication of cathode crystals with the most thermally stable facets.
Adsorption behaviors and vibrational spectra of hydrogen peroxide molecules at quartz/water interfaces
Feb 22, 2017   Physical Chemistry Chemical Physics : PCCP
Lv Y, Wang X, Yu X, Zheng S, Wang S, Zhang Y, Du H
Feb 22, 2017   Frontiers In Microbiology
Portugal B, Motta FN, Correa AF, Nolasco DO, de Almeida H, Magalhães KG, Atta AL, Vieira FD, Bastos IM, Santana JM
Feb 22, 2017
Frontiers In Microbiology
UNASSIGNED: Tuberculosis (TB) is a disease that leads to death over 1 million people per year worldwide and the biological mediators of this pathology are poorly established, preventing the implementation of effective therapies to improve outcomes in TB. Host-bacterium interaction is a key step to TB establishment and the proteases produced by these microorganisms seem to facilitate bacteria invasion, migration and host immune response evasion. We presented, for the first time, the identification, biochemical characterization, molecular dynamics (MDs) and immunomodulatory properties of a prolyl oligopeptidase (POP) from
Integrated view of internal friction in unfolded proteins from single-molecule FRET, contact quenching, theory, and simulations
Feb 22, 2017   Proceedings Of The National Academy Of Sciences Of The United States Of America
Soranno A, Holla A, Dingfelder F, Nettels D, Makarov DE, Schuler B
Integrated view of internal friction in unfolded proteins from single-molecule FRET, contact quenching, theory, and simulations
Feb 22, 2017
Proceedings Of The National Academy Of Sciences Of The United States Of America
UNASSIGNED: Internal friction is an important contribution to protein dynamics at all stages along the folding reaction. Even in unfolded and intrinsically disordered proteins, internal friction has a large influence, as demonstrated with several experimental techniques and in simulations. However, these methods probe different facets of internal friction and have been applied to disparate molecular systems, raising questions regarding the compatibility of the results. To obtain an integrated view, we apply here the combination of two complementary experimental techniques, simulations, and theory to the same system: unfolded protein L. We use single-molecule Förster resonance energy transfer (FRET) to measure the global reconfiguration dynamics of the chain, and photoinduced electron transfer (PET), a contact-based method, to quantify the rate of loop formation between two residues. This combination enables us to probe unfolded-state dynamics on different length scales, corresponding to different parts of the intramolecular distance distribution. Both FRET and PET measurements show that internal friction dominates unfolded-state dynamics at low denaturant concentration, and the results are in remarkable agreement with recent large-scale molecular dynamics simulations using a new water model. The simulations indicate that intrachain interactions and dihedral angle rotation correlate with the presence of internal friction, and theoretical models of polymer dynamics provide a framework for interrelating the contribution of internal friction observed in the two types of experiments and in the simulations. The combined results thus provide a coherent and quantitative picture of internal friction in unfolded proteins that could not be attained from the individual techniques.
Anatase (101)-like Structural Model Revealed for Metastable Rutile TiO2(011) Surface
Feb 23, 2017   ACS Applied Materials & Interfaces
Xu M, Shao S, Gao B, Lv J, Li Q, Wang Y, Wang H, Zhang L, Ma Y
Anatase (101)-like Structural Model Revealed for Metastable Rutile TiO2(011) Surface
Feb 23, 2017
ACS Applied Materials & Interfaces
Titanium dioxide has been widely used as efficient transition metal oxide photocatalyst. However, its photocatalytic activity is limited to ultraviolet spectrum range due to the deficient large bandgap beyond 3 eV. Efforts towards to reduce the bandgap for achieving a broader spectrum range of light absorption are attempted with a success on the experimental synthesis of dopant-free metastable surface structure of rutile-type TiO2 (011) 21. This new surface phase possesses a much reduced bandgap of ~2.1 eV, showing a great potential for an excellent photocatalyst covering a wide range of visible light. There is an urge to establish the atomistic structure of this metastable surface for understanding the physical cause for the bandgap reduction and for future design of better photocatalyst. We here report the computational investigations in an effort to unravel this surface structure via swarm structure-searching simulations. The established structure adopts the anatase (101)-like structure model, where the topmost two-fold O atoms form a quasi-hexagonal surface pattern, and bonded with unsaturated five-fold and four-fold Ti atoms in the next layer. The predicted anatase (101)-like surface model can naturally explain the experimental observation of STM image, the electronic bandgap, and the oxidation state of Ti4+. Dangling bonds on the anatase (101)-like surface are rich, making it a superior photocatalyst. First-principles molecular dynamics simulations has approved the high photocatalystic activity by showing that water and formic acid molecules dissociate spontaneously on this anatase (101)-like surface.
Molecular mechanisms of cooperative binding of transcription factors Runx1-CBFβ-Ets1 on the TCRα gene enhancer
Feb 23, 2017   PloS One
Kasahara K, Shiina M, Fukuda I, Ogata K, Nakamura H
Molecular mechanisms of cooperative binding of transcription factors Runx1-CBFβ-Ets1 on the TCRα gene enhancer
Feb 23, 2017
PloS One
Ets1 is an essential transcription factor (TF) for several important physiological processes, including cell proliferation and differentiation. Its recognition of the enhancer region of the TCRα gene is enhanced by the cooperative binding of the Runx1-CBFβ heterodimer, with the cancelation of phosphorylation-dependent autoinhibition. The detailed mechanism of this interesting cooperativity between Ets1 and the Runx1-CBFβ heterodimer is still largely unclear. Here, we investigated the molecular mechanisms of this cooperativity, by using molecular dynamics simulations. Consequently, we detected high flexibility of the loop region between the HI2 and H1 helices of Ets1. Upon Runx1-CBFβ heterodimer binding, this loop transiently adopts various sub-stable conformations in its interactions with the DNA. In addition, a network analysis suggested an allosteric pathway in the molecular assembly and identified some key residues that coincide with previous experimental studies. Our simulations suggest that the cooperative binding of Ets1 and the Runx1-CBFβ heterodimer alters the DNA conformation and induces sub-stable conformations of the HI2-H1 loop of Ets1. This phenomenon increases the flexibility of the regulatory module, including the HI2 helix, and destabilizes the inhibitory form of this module. Thus, we hypothesize that this effect facilitates Ets1-DNA binding and prevents the phosphorylation-dependent DNA binding autoinhibition.
PEGylated graphene oxide elicits strong immunological responses despite surface passivation
Feb 24, 2017   Nature Communications
Luo N, Weber JK, Wang S, Luan B, Yue H, Xi X, Du J, Yang Z, Wei W, Zhou R, Ma G
PEGylated graphene oxide elicits strong immunological responses despite surface passivation
Feb 24, 2017
Nature Communications
Engineered nanomaterials promise to transform medicine at the bio-nano interface. However, it is important to elucidate how synthetic nanomaterials interact with critical biological systems before such products can be safely utilized in humans. Past evidence suggests that polyethylene glycol-functionalized (PEGylated) nanomaterials are largely biocompatible and elicit less dramatic immune responses than their pristine counterparts. We here report results that contradict these findings. We find that PEGylated graphene oxide nanosheets (nGO-PEGs) stimulate potent cytokine responses in peritoneal macrophages, despite not being internalized. Atomistic molecular dynamics simulations support a mechanism by which nGO-PEGs preferentially adsorb onto and/or partially insert into cell membranes, thereby amplifying interactions with stimulatory surface receptors. Further experiments demonstrate that nGO-PEG indeed provokes cytokine secretion by enhancing integrin β
Hydrophilicities of amylose and natural cellulose are regulated by the linkage between sugar rings
Feb 24, 2017   Nanoscale
Bao Y, Xu D, Qian L, Zhao L, Lu ZY, Cui S
Hydrophilicities of amylose and natural cellulose are regulated by the linkage between sugar rings
Feb 24, 2017
Nanoscale
Comparative studies of single molecule force spectroscopy and molecular dynamics simulations indicate that natural cellulose is more hydrophobic than amylose at the single-chain level, implying that the hydrophobicities of these polymeric isomers are regulated by only one parameter in the chains, the linkage between the sugar rings.
Molecular dynamics simulations reveal ligand-controlled positioning of a peripheral protein complex in membranes
Feb 24, 2017   Nature Communications
Ryckbosch SM, Wender PA, Pande VS
Molecular dynamics simulations reveal ligand-controlled positioning of a peripheral protein complex in membranes
Feb 24, 2017
Nature Communications
Bryostatin is in clinical trials for Alzheimer's disease, cancer, and HIV/AIDS eradication. It binds to protein kinase C competitively with diacylglycerol, the endogenous protein kinase C regulator, and plant-derived phorbol esters, but each ligand induces different activities. Determination of the structural origin for these differing activities by X-ray analysis has not succeeded due to difficulties in co-crystallizing protein kinase C with relevant ligands. More importantly, static, crystal-lattice bound complexes do not address the influence of the membrane on the structure and dynamics of membrane-associated proteins. To address this general problem, we performed long-timescale (400-500 µs aggregate) all-atom molecular dynamics simulations of protein kinase C-ligand-membrane complexes and observed that different protein kinase C activators differentially position the complex in the membrane due in part to their differing interactions with waters at the membrane inner leaf. These new findings enable new strategies for the design of simpler, more effective protein kinase C analogs and could also prove relevant to other peripheral protein complexes.Natural supplies of bryostatin, a compound in clinical trials for Alzheimer's disease, cancer, and HIV, are scarce. Here, the authors perform molecular dynamics simulations to understand how bryostatin interacts with membrane-bound protein kinase C, offering insights for the design of bryostatin analogs.
GIGANTEA is a co-chaperone which facilitates maturation of ZEITLUPE in the Arabidopsis circadian clock
Feb 24, 2017   Nature Communications
Cha JY, Kim J, Kim TS, Zeng Q, Wang L, Lee SY, Kim WY, Somers DE
GIGANTEA is a co-chaperone which facilitates maturation of ZEITLUPE in the Arabidopsis circadian clock
Feb 24, 2017
Nature Communications
Circadian clock systems help establish the correct daily phasing of the behavioral, developmental, and molecular events needed for the proper coordination of physiology and metabolism. The circadian oscillator comprises transcription-translation feedback loops but also requires post-translational processes that regulate clock protein homeostasis. GIGANTEA is a unique plant protein involved in the maintenance and control of numerous facets of plant physiology and development. Through an unknown mechanism GIGANTEA stabilizes the F-box protein ZEITLUPE, a key regulator of the circadian clock. Here, we show that GIGANTEA has general protein chaperone activity and can act to specifically facilitate ZEITLUPE maturation into an active form in vitro and in planta. GIGANTEA forms a ternary complex with HSP90 and ZEITLUPE and its co-chaperone action synergistically enhances HSP90/HSP70 maturation of ZEITLUPE in vitro. These results identify a molecular mechanism for GIGANTEA activity that can explain its wide-ranging role in plant biology.The plant-specific GIGANTEA protein regulates the circadian clock by stabilizing the F-box protein ZEITLUPE via an unknown mechanism. Here Cha et al. show that GIGANTEA has intrinsic chaperone activity and can facilitate ZEITLUPE maturation by acting synergistically with HSP90.
Drastic Compensation of the Electronic and Solvation Effects on the ATP Hydrolysis Revealed Through a Large-Scale QM/MM Simulations Combined with a Theory of Solutions
Feb 22, 2017   The Journal Of Physical Chemistry. B
Takahashi H, Umino S, Miki Y, Ishizuka R, Maeda S, Morita A, Suzuki M, Matubayasi N
Drastic Compensation of the Electronic and Solvation Effects on the ATP Hydrolysis Revealed Through a Large-Scale QM/MM Simulations Combined with a Theory of Solutions
Feb 22, 2017
The Journal Of Physical Chemistry. B
UNASSIGNED: Hydrolysis of adenosine triphosphate (ATP) is the "energy source" for a variety of biochemical processes. In the present work, we address key features of ATP hydrolysis: the relatively moderate value (about -10 kcal/mol) of the standard free energy ΔG
Self-assembly of nanoparticles into biomimetic capsid-like nanoshells
Feb 21, 2017   Nature Chemistry Add nature.com free-link Cancel
Yang M, Chan H, Zhao G, Bahng JH, Zhang P, Král P, Kotov NA
Self-assembly of nanoparticles into biomimetic capsid-like nanoshells
Feb 21, 2017
Nature Chemistry
UNASSIGNED: Nanoscale compartments are one of the foundational elements of living systems. Capsids, carboxysomes, exosomes, vacuoles and other nanoshells easily self-assemble from biomolecules such as lipids or proteins, but not from inorganic nanomaterials because of difficulties with the replication of spherical tiling. Here we show that stabilizer-free polydispersed inorganic nanoparticles (NPs) can spontaneously organize into porous nanoshells. The association of water-soluble CdS NPs into self-limited spherical capsules is the result of scale-modified electrostatic, dispersion and other colloidal forces. They cannot be accurately described by the Derjaguin-Landau-Vervey-Overbeek theory, whereas molecular-dynamics simulations with combined atomistic and coarse-grained description of NPs reveal the emergence of nanoshells and some of their stabilization mechanisms. Morphology of the simulated assemblies formed under different conditions matched nearly perfectly the transmission electron microscopy tomography data. This study bridges the gap between biological and inorganic self-assembling nanosystems and conceptualizes a new pathway to spontaneous compartmentalization for a wide range of inorganic NPs including those existing on prebiotic Earth.
An Atypical Thioredoxin Imparts Early Resistance to Sugarcane Mosaic Virus in Maize
Feb 20, 2017   Molecular Plant
Liu Q, Liu H, Gong Y, Tao Y, Jiang L, Zuo W, Yang Q, Ye J, Lai J, Wu J, Lübberstedt T, Xu M
An Atypical Thioredoxin Imparts Early Resistance to Sugarcane Mosaic Virus in Maize
Feb 20, 2017
Molecular Plant
UNASSIGNED: Sugarcane mosaic virus (SCMV) disease causes substantial losses of grain yield and forage biomass in susceptible maize worldwide. A major quantitative trait locus, Scmv1, has been identified to impart strong resistance to SCMV at early infection stage. Here, we demonstrate that ZmTrxh, encoding an atypical h-type thioredoxin, is the causal gene at Scmv1, and that its transcript abundance correlated strongly with maize resistance to SCMV. ZmTrxh alleles, whether they are resistant or susceptible, share the identical coding/proximal promoter regions, but vary in the upstream regulatory regions. ZmTrxh lacks two canonical cysteines in the thioredoxin active-site motif and exists uniquely in maize genome. Because of this, ZmTrxh is unable to reduce disulfide bridges, but possesses a strong molecular chaperone-like activity. ZmTrxh is dispersed in maize cytoplasm to suppress SCMV viral RNA accumulation. Moreover, ZmTrxh-mediated maize resistance to SCMV showed no obvious correlation with the SA- and JA-related defense signaling pathways. Altogether, ZmTrxh exhibits a distinct defense profile in maize resistance to SCMV, differing from previously characterized dominant or recessive potyvirus resistance genes. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.
Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations
Feb 20, 2017   Molecular BioSystems
Cao H, Sun Y, Wang L, Zhao C, Fu J, Zhang A
Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations
Feb 20, 2017
Molecular BioSystems
UNASSIGNED: Polybrominated diphenyl ethers (PBDEs), one typical type of persistent environmental contaminant, have toxicological effects such as disrupting thyroid homeostasis in the human body. The high binding affinities of hydroxylated metabolites of PBDEs (OH-PBDEs) with transthyretin (TTR) were considered to be one major reason for their extraordinary capacity of passing through the blood-brain barrier via competitive thyroid hormone (T4) transport protein binding. Recent findings showed that sulfated PBDEs can be formed in human liver cytosol as phase-II metabolites. However, experimentally determined data for the TTR binding potential of the sulfated PBDEs are still not available. Therefore, molecular docking and molecular dynamics (MD) simulations were employed in the present study to probe the molecular basis of TTR interacting with hydroxylated and sulfated PBDEs at the atomic level. The docking scores of LeDock were used to construct the structure-based predictive model. The calculated results showed that the sulfated PBDEs have stronger affinity for TTR than the corresponding OH-PBDEs. Further analysis of structural characteristics based on MD simulations indicated that upon the binding of PBDE metabolites, the stability of TTR was enhanced and the dissociation rate of the tetrameric protein structure was potentially decreased. Subsequent binding free energy calculations implied that van der Waals interactions are the dominant forces for the binding of these metabolites of PBDEs at the T4 site of TTR. The residues Ser117/Ser117' and Lys15/Lys15' were identified, by both residue energy decomposition and computational alanine-scanning mutagenesis methods, as key residues which play an important role in determining the binding orientations of the -OSO
HSP90 Shapes the Consequences of Human Genetic Variation
Feb 20, 2017   Cell
Karras GI, Yi S, Sahni N, Fischer M, Xie J, Vidal M, D'Andrea AD, Whitesell L, Lindquist S
HSP90 Shapes the Consequences of Human Genetic Variation
Feb 20, 2017
Cell
UNASSIGNED: HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. By mining data for >1,500 disease-causing mutants, we found a strong correlation between reduced phenotypic severity and a dominant (HSP90 ≥ HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function. In contrast, the function of less severe mutants was preserved by a dominant increase in HSP90 binding. Reducing HSP90's buffering capacity with inhibitors or febrile temperatures destabilized HSP90-buffered mutants, exacerbating FA-related chemosensitivities. Strikingly, a compensatory FANCA somatic mutation from an "experiment of nature" in monozygotic twins both prevented anemia and reduced HSP90 binding. These findings provide one plausible mechanism for the variable expressivity and environmental sensitivity of genetic diseases. Copyright © 2017 Elsevier Inc. All rights reserved.
Evaluation of molecular chaperone drug function: Regorafenib and β-cyclodextrins
Feb 19, 2017   Colloids And Surfaces. B, Biointerfaces
Hu X, Sun M, Li Y, Tang G
Evaluation of molecular chaperone drug function: Regorafenib and β-cyclodextrins
Feb 19, 2017
Colloids And Surfaces. B, Biointerfaces
UNASSIGNED: Regorafenib (RG) was an oral multi-kinase inhibitor with poor water solubility. In order to enhance the drug's solubility, dissolution and bioavailability, the binary molecular chaperone drug between RG and β-cyclodetrin (β-CD) had prepared by co-crystallization. The structure of RG-β-CD was characterized by thermal analysis, powder X-ray diffraction, infrared spectroscopy and nuclear magnetic resonance. Phase-solubility study revealed the higher solubility and complexing ability of β-CDwith RG.The solubility and dissolution of RG-β-CD was significantly enhanced in pH 1.2 medium, pH 6.8 PBS buffer solution and distilled water compared to RG. In vivo distribution and antitumor studies revealed that the bioavailability of RG-β-CD was increased when β-CD mated with RG. Therefore, these findings could provide a suitable pharmaceutical dosage to enhanced therapeutic activity. Copyright © 2017 Elsevier B.V. All rights reserved.
The Influence of Anion Shape on the Electrical Double Layer Microstructure and Capacitance of Ionic Liquids-Based Supercapacitors by Molecular Simulations
Feb 17, 2017   Molecules (Basel, Switzerland)
Chen M, Li S, Feng G
The Influence of Anion Shape on the Electrical Double Layer Microstructure and Capacitance of Ionic Liquids-Based Supercapacitors by Molecular Simulations
Feb 17, 2017
Molecules (Basel, Switzerland)
UNASSIGNED: Room-temperature ionic liquids (RTILs) are an emerging class of electrolytes for supercapacitors. In this work, we investigate the effects of different supercapacitor models and anion shape on the electrical double layers (EDLs) of two different RTILs: 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([Emim][Tf₂N]) and 1-ethyl-3-methylimidazolium 2-(cyano)pyrrolide ([Emim][CNPyr]) by molecular dynamics (MD) simulation. The EDL microstructure is represented by number densities of cations and anions, and the potential drop near neutral and charged electrodes reveal that the supercapacitor model with a single electrode has the same EDL structure as the model with two opposite electrodes. Nevertheless, the employment of the one-electrode model without tuning the bulk density of RTILs is more time-saving in contrast to the two-electrode one. With the one-electrode model, our simulation demonstrated that the shapes of anions significantly imposed effects on the microstructure of EDLs. The EDL differential capacitance vs. potential (C-V) curves of [Emim][CNPyr] electrolyte exhibit higher differential capacitance at positive potentials. The modeling study provides microscopic insight into the EDLs structure of RTILs with different anion shapes.
Chromatin remodeller Fun30
Feb 20, 2017   Nature Communications
Lee J, Shik Choi E, David Seo H, Kang K, Gilmore JM, Florens L, Washburn MP, Choe J, Workman JL, Lee D
Chromatin remodeller Fun30
Feb 20, 2017
Nature Communications
UNASSIGNED: Previous studies have revealed that nucleosomes impede elongation of RNA polymerase II (RNAPII). Recent observations suggest a role for ATP-dependent chromatin remodellers in modulating this process, but direct in vivo evidence for this is unknown. Here using fission yeast, we identify Fun30
Proteomic analysis of exported chaperone/co-chaperone complexes of P. falciparum reveals an array of complex protein-protein interactions
Feb 20, 2017   Scientific Reports
Zhang Q, Ma C, Oberli A, Zinz A, Engels S, Przyborski JM
Proteomic analysis of exported chaperone/co-chaperone complexes of P. falciparum reveals an array of complex protein-protein interactions
Feb 20, 2017
Scientific Reports
UNASSIGNED: Malaria parasites modify their human host cell, the mature erythrocyte. This modification is mediated by a large number of parasite proteins that are exported to the host cell, and is also the underlying cause for the pathology caused by malaria infection. Amongst these proteins are many Hsp40 co-chaperones, and a single Hsp70. These proteins have been implicated in several processes in the host cell, including a potential role in protein transport, however the further molecular players in this process remain obscure. To address this, we have utilized chemical cross-linking followed by mass spectrometry and immunoblotting to isolate and characterize proteins complexes containing an exported Hsp40 (PFE55), and the only known exported Hsp70 (PfHsp70x). Our data reveal that both of these proteins are contained in high molecular weight protein complexes. These complexes are found both in the infected erythrocyte, and within the parasite-derived compartment referred to as the parasitophorous vacuole. Surprisingly, our data also reveal an association of PfHsp70x with components of PTEX, a putative protein translocon within the membrane of the parasitophorous vacuole. Our results suggest that the P. falciparum- infected human erythrocyte contains numerous high molecular weight protein complexes, which may potentially be involved in host cell modification.
Comparison of Methods for Determining the Mechanical Properties of Semiconducting Polymer Films for Stretchable Electronics
Feb 21, 2017   ACS Applied Materials & Interfaces
Rodriquez D, Kim JH, Root SE, Fei Z, Boufflet P, Heeney M, Kim TS, Lipomi DJ
Comparison of Methods for Determining the Mechanical Properties of Semiconducting Polymer Films for Stretchable Electronics
Feb 21, 2017
ACS Applied Materials & Interfaces
UNASSIGNED: This paper describes a comparison of two characterization techniques for determining the mechanical properties of thin-film organic semiconductors for applications in soft electronics. In the first method, the film is supported by water (film-on-water, FOW), and a stress-strain curve is obtained using a direct tensile test. In the second method, the film is supported by an elastomer (film-on-elastomer, FOE), and is subjected to three tests to reconstruct the key features of the stress-strain curve: the buckling test (tensile modulus), the onset of buckling (yield point), and the crack-onset strain (strain at fracture). The specimens used for the comparison are four poly(3-hexylthiophene) (P3HT) samples of increasing molecular weight (Mn = 15, 40, 63, and 80 kDa). The methods produced qualitatively similar results for mechanical properties including the tensile modulus, the yield point, and the strain at fracture. The agreement was not quantitative because of differences in mode of loading (tension vs. compression), strain rate, and processing between the two methods. Experimental results are corroborated by coarse-grained molecular dynamics simulations, which lead to the conclusion that in low molecular weight samples (Mn = 15 kDa), fracture occurs by chain pullout. Conversely, in high molecular weight samples (Mn > 25kDa), entanglements concentrate the stress to few chains; this concentration is consistent with chain scission as the dominant mode of fracture. Our results provide a basis for comparing mechanical properties that have been measured by these two techniques, and provide mechanistic insight into fracture modes in this class of materials.
Ligand-promoted protein folding by biased kinetic partitioning
Feb 20, 2017   Nature Chemical Biology Add nature.com free-link Cancel
Hingorani KS, Metcalf MC, Deming DT, Garman SC, Powers ET, Gierasch LM
Ligand-promoted protein folding by biased kinetic partitioning
Feb 20, 2017
Nature Chemical Biology
UNASSIGNED: Protein folding in cells occurs in the presence of high concentrations of endogenous binding partners, and exogenous binding partners have been exploited as pharmacological chaperones. A combined mathematical modeling and experimental approach shows that a ligand improves the folding of a destabilized protein by biasing the kinetic partitioning between folding and alternative fates (aggregation or degradation). Computationally predicted inhibition of test protein aggregation and degradation as a function of ligand concentration are validated by experiments in two disparate cellular systems.
Mechanistic basis for the recognition of a misfolded protein by the molecular chaperone Hsp90
Feb 20, 2017   Nature Structural & Molecular Biology Add nature.com free-link Cancel
Oroz J, Kim JH, Chang BJ, Zweckstetter M
Mechanistic basis for the recognition of a misfolded protein by the molecular chaperone Hsp90
Feb 20, 2017
Nature Structural & Molecular Biology
UNASSIGNED: The critical toxic species in over 40 human diseases are misfolded proteins. Their interaction with molecular chaperones such as Hsp90, which preferentially interacts with metastable proteins, is essential for the blocking of disease progression. Here we used nuclear magnetic resonance (NMR) spectroscopy to determine the three-dimensional structure of the misfolded cytotoxic monomer of the amyloidogenic human protein transthyretin, which is characterized by the release of the C-terminal β-strand and perturbations of the A-B loop. The misfolded transthyretin monomer, but not the wild-type protein, binds to human Hsp90. In the bound state, the Hsp90 dimer predominantly populates an open conformation, and transthyretin retains its globular structure. The interaction surface for the transthyretin monomer comprises the N-terminal and middle domains of Hsp90 and overlaps with that of the Alzheimer's-disease-related protein tau. Taken together, the data suggest that Hsp90 uses a mechanism for the recognition of aggregation-prone proteins that is largely distinct from those of other Hsp90 clients.
Graphene-Induced Pore Formation on Cell Membranes
Feb 20, 2017   Scientific Reports
Duan G, Zhang Y, Luan B, Weber JK, Zhou RW, Yang Z, Zhao L, Xu J, Luo J, Zhou R
Graphene-Induced Pore Formation on Cell Membranes
Feb 20, 2017
Scientific Reports
UNASSIGNED: Examining interactions between nanomaterials and cell membranes can expose underlying mechanisms of nanomaterial cytotoxicity and guide the design of safer nanomedical technologies. Recently, graphene has been shown to exhibit potential toxicity to cells; however, the molecular processes driving its lethal properties have yet to be fully characterized. We here demonstrate that graphene nanosheets (both pristine and oxidized) can produce holes (pores) in the membranes of A549 and Raw264.7 cells, substantially reducing cell viability. Electron micrographs offer clear evidence of pores created on cell membranes. Our molecular dynamics simulations reveal that multiple graphene nanosheets can cooperate to extract large numbers of phospholipids from the membrane bilayer. Strong dispersion interactions between graphene and lipid-tail carbons result in greatly depleted lipid density within confined regions of the membrane, ultimately leading to the formation of water-permeable pores. This cooperative lipid extraction mechanism for membrane perforation represents another distinct process that contributes to the molecular basis of graphene cytotoxicity.
The dynamic conductance response and mechanics-modulated memristive behavior of the Azurin monolayer under cyclic loads
Feb 17, 2017   Physical Chemistry Chemical Physics : PCCP
Zhang X, Shao J, Chen Y, Chen W, Yu J, Wang B, Zheng Y
The dynamic conductance response and mechanics-modulated memristive behavior of the Azurin monolayer under cyclic loads
Feb 17, 2017
Physical Chemistry Chemical Physics : PCCP
UNASSIGNED: Azurin (Az) has been considered as the research hotspot in molecular electronics, as well as a promising material for building functional devices on the molecular scale because of its special electrical properties and force-dependent conductance effects. Here we carry out an in-depth investigation combined with molecular scale experiments, molecular dynamics simulations, first-principles calculations and theoretical models to reveal the dynamic conductance response of the Az monolayer under cyclic mechanical loading. Experimentally, the conductance of the Az monolayer under continuous cyclic loads was recorded using a conductive atomic force microscope. Our results demonstrate the strong nonlinear force-dependence and significant time-delayed characteristics, which distinctly differ from the results obtained under stepwise loading. It is also found that the period and amplitude of cyclic loads have a great impact on the magnitude, peak value and change rate of the current. The regular dynamic response of the Az conductance under mechanical force looks like a type of memristive behavior, which is defined as mechanics-modulated memristive behavior in this work. In order to verify these peculiar experimental results, we employed both molecular dynamics simulations and first-principles calculations to analyze the structural deformation and molecular orbitals of Az under cyclic loads. A phenomenological model is also established to explain experimental findings and further illustrate mechanics-modulated memristive behavior.

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