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Protein Folding
Computational and experimental prediction of molecules involved in the anti-melanoma action of berberine
Jul 21, 2017   Journal Of Ethnopharmacology
Bin Liu , Fu XQ, Li T, Su T, Guo H, Zhu PL, Kai-Wing Tse A, Liu SM, Yu ZL
Computational and experimental prediction of molecules involved in the anti-melanoma action of berberine
Jul 21, 2017
Journal Of Ethnopharmacology
Berberine (BBR) is a naturally occurring alkaloid compound that can be found in Chinese medicinal herbs such as Rhizoma Coptidis and Phellodendri Cortex. These BBR containing herbs are commonly used by Chinese medicine doctors to treat cancers including melanoma. In this study, we explored proteins potentially involved in the anti-melanoma effects of BBR using an integrative computational and experimental approach. Target proteins of BBR were predicted using the reverse pharmacophore screening, molecular docking and molecular dynamics. Anti-melanoma activities of BBR in melanoma cells were examined by MTT and EdU proliferation assays. Effects of BBR on activities of target proteins in melanoma cells were examined by Western blotting or fluorescence assay. Ten proteins implicated in cancer and with high fit-score in the reverse pharmacophore screening were selected as potential targets of BBR. Molecular docking and molecular dynamics revealed that BBR could stably bind to four of the ten proteins, namely 3-phosphoinositide-dependent protein kinase 1 (PDK1), glucocorticoid receptor (GR), p38 mitogen-activated protein kinase (p38) and dihydroorotate dehydrogenase (DHODH). Cellular experiments showed that BBR inhibited cell proliferation, increased the phosphorylation of GR and p38, and inhibited the activity of DHODH in A375 human melanoma cells. These findings suggest that p38, GR and DHODH are potentially involved in the anti-melanoma action of BBR. This study provided a chemical and pharmacological justification for the clinical use of BBR-containing herbs in melanoma treatment. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
How cholesteryl ester transfer protein can also be a potential triglyceride transporter
Jul 22, 2017   Scientific Reports
Chirasani VR, Senapati S
How cholesteryl ester transfer protein can also be a potential triglyceride transporter
Jul 22, 2017
Scientific Reports
CETP transfers cholesteryl esters (CEs) and triglycerides (TGs) between different lipoproteins and came in limelight as a drug-target against CVD. In the search for detailed mechanism of lipid transfer through CETP, enormous effort is devoted employing crystallographic, cryo-EM, and Molecular Dynamics (MD) studies. However, these studies primarily focused on CE-bound CETP structure and CE transfer mechanism. With the reported correlation that CETP looses significant CE transfer activity upon inhibiting TG transfer, it is of tremendous importance to understand the structure and dynamics of TG-bound CETP. Our results from large-scale all-atom and coarse-grained MD simulations show that CETP can accommodate two TG molecules in parallel N-N orientation with TG oleate chains majorly attaining the tuning-fork conformation. In TG-bound form, CETP not only maintained its secondary structures but also exhibited similar bending-twisting motions as reported for CE-CETP crystal structure. Obtained structural information are further validated by correlating to available functional data of 2-8 fold slower transfer rate of TG through CETP, where we show that TGs make 20% additional contacts with CETP compared to CEs. Identified CETP residues facilitating TG binding also match very well with reported mutagenesis data. The study could accelerate the drug-designing processes to combat CETP functionality and CVD.
Species A rotavirus NSP3 acquires its translation inhibitory function prior to stable dimer formation
Jul 24, 2017   PloS One
Contreras-Treviño HI, Reyna-Rosas E, León-Rodríguez R, Ruiz-Ordaz BH, Dinkova TD, Cevallos AM, Padilla-Noriega L
Species A rotavirus NSP3 acquires its translation inhibitory function prior to stable dimer formation
Jul 24, 2017
PloS One
Species A rotavirus non-structural protein 3 (NSP3) is a translational regulator that inhibits or, under some conditions, enhances host cell translation. NSP3 binds to the translation initiation factor eIF4G1 and evicts poly-(A) binding protein (PABP) from eIF4G1, thus inhibiting translation of polyadenylated mRNAs, presumably by disrupting the effect of PABP bound to their 3'-ends. NSP3 has a long coiled-coil region involved in dimerization that includes a chaperone Hsp90-binding domain (HS90BD). We aimed to study the role in NSP3 dimerization of a segment of the coiled-coil region adjoining the HS90BD. We used a vaccinia virus system to express NSP3 with point mutations in conserved amino acids in the coiled-coil region and determined the effects of these mutations on translation by metabolic labeling of proteins as well as on accumulation of stable NSP3 dimers by non-dissociating Western blot, a method that separates stable NSP3 dimers from the monomer/dimerization intermediate forms of the protein. Four of five mutations reduced the total yield of NSP3 and the formation of stable dimers (W170A, K171E, R173E and R187E:K191E), whereas one mutation had the opposite effects (Y192A). Treatment with the proteasome inhibitor MG132 revealed that stable NSP3 dimers and monomers/dimerization intermediates are susceptible to proteasome degradation. Surprisingly, mutants severely impaired in the formation of stable dimers were still able to inhibit host cell translation, suggesting that NSP3 dimerization intermediates are functional. Our results demonstrate that rotavirus NSP3 acquires its function prior to stable dimer formation and remain as a proteasome target throughout dimerization.
BAG3 plays a central role in proteostasis in the heart
Jul 24, 2017   The Journal Of Clinical Investigation
Mizushima W, Sadoshima J
BAG3 plays a central role in proteostasis in the heart
Jul 24, 2017
The Journal Of Clinical Investigation
Proteinopathies are characterized by the accumulation of misfolded proteins, which ultimately interfere with normal cell function. While neurological diseases, such as Huntington disease and Alzheimer disease, are well-characterized proteinopathies, cardiac diseases have recently been associated with alterations in proteostasis. In this issue of the JCI, Fang and colleagues demonstrate that mice with cardiac-specific deficiency of the co-chaperone protein BCL2-associated athanogene 3 (BAG3) develop dilated cardiomyopathy that is associated with a destabilization of small HSPs as the result of a disrupted interaction between BAG3 and HSP70. Together, the results of this study suggest that strategies to upregulate BAG3 during cardiac dysfunction may be beneficial.
Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy
Jul 24, 2017   The Journal Of Clinical Investigation
Fang X, Bogomolovas J, Wu T, Zhang W, Liu C,   . . . . . .   , Lange S, Ouyang K, Peterson KL, Evans SM, Chen J
Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy
Jul 24, 2017
The Journal Of Clinical Investigation
Defective protein quality control (PQC) systems are implicated in multiple diseases. Molecular chaperones and co-chaperones play a central role in functioning PQC. Constant mechanical and metabolic stress in cardiomyocytes places great demand on the PQC system. Mutation and downregulation of the co-chaperone protein BCL-2-associated athanogene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and the mechanisms by which the E455K mutation leads to DCM remain obscure. Here, we found that cardiac-specific Bag3-KO and E455K-knockin mice developed DCM. Comparable phenotypes in the 2 mutants demonstrated that the E455K mutation resulted in loss of function. Further experiments revealed that the E455K mutation disrupted the interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a subset of proteins required for cardiomyocyte function was enriched in the insoluble fraction. Together, these observations suggest that interaction between BAG3 and HSP70 is essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide insight into heart failure caused by defects in BAG3 pathways and suggest that increasing BAG3 protein levels may be of therapeutic benefit in heart failure.
Evolution of Aggregate Structure in Solutions of Anionic Monorhamnolipids: Experimental and Computational Results
Jul 24, 2017   Langmuir : The ACS Journal Of Surfaces And Colloids
Eismin RJ, Munusamy E, Kegel LL, Hogan DE, Maier RM, Schwartz SD, Pemberton JE
Evolution of Aggregate Structure in Solutions of Anionic Monorhamnolipids: Experimental and Computational Results
Jul 24, 2017
Langmuir : The ACS Journal Of Surfaces And Colloids
The evolution of solution aggregates of the anionic form of the native monorhamnolipid (mRL) mixture produced by Pseudomonas aeruginosa ATCC 9027 is explored at pH 8.0 using both experimental and computational approaches. Experiments utilizing surface tension measurements, dynamic light scattering, and both steady-state and time-resolved fluorescence spectroscopy reveal solution aggregation properties. All-atom molecular dynamics simulations on self-assemblies of the most abundant monorhamnolipid molecule, l-rhamnosyl-β-hydroxydecanoyl-β-hydroxydecanoate (Rha-C10-C10), in its anionic state explore the formation of aggregates and the role of hydrogen bonding, substantiating the experimental results. At pH 8.0, at concentrations above the critical aggregation concentration of 201 μM but below ∼7.5 mM, small premicelles exist in solution; above ∼7.5 mM, micelles with hydrodynamic radii of ∼2.5 nm dominate, although two discrete populations of larger lamellar aggregates (hydrodynamic radii of ∼10 and 90 nm) are also present in solution in much smaller number densities. The critical aggregation number for the micelles is determined to be ∼26 monomers/micelle using fluorescence quenching measurements, with micelles gradually increasing in size with monorhamnolipid concentration. Molecular dynamics simulations on systems with between 10 and 100 molecules of Rha-C10-C10 indicate the presence of stable premicelles of seven monomers with the most prevalent micelle being ∼25 monomers and relatively spherical. A range of slightly larger micelles of comparable stability can also exist that become increasing elliptical with increasing monomer number. Intermolecular hydrogen bonding is shown to play a significant role in stabilization of these aggregates. In total, the computational results are in excellent agreement with the experimental results.
Gastroresistant oral peptide for fluorescence imaging of colonic inflammation
Jul 23, 2017   Journal Of Controlled Release : Official Journal Of The Controlled Release Society
Luciani P, de Mendoza AE, Casalini T, Lang S, Atrott K, Spalinger MR, Pratsinis A, Sobek J, Frey-Wagner I, Schumacher J, Leroux JC, Rogler G
Gastroresistant oral peptide for fluorescence imaging of colonic inflammation
Jul 23, 2017
Journal Of Controlled Release : Official Journal Of The Controlled Release Society
The use of molecular markers for inflammation in the gastrointestinal tract could empower optical imaging modalities for early diagnosis and eventually personalized timely treatments. A major hurdle to the widespread use of functional fluorescence imaging is the absence of suitable contrast agents, in particular to be administered via the oral route due to the usual proteolytic susceptibility of the biomarkers. By designing a retro-inverso peptide, starting from a previously described sequence specific for N-cadherin, we achieved resistance to gastrointestinal degradation and even slightly improved specificity towards the target, both in ex vivo and in vivo experimental colitis. Simulations at fundamental molecular level suggested that the introduced retro-inverso modifications did not affect the folding of the peptide, leaving its ability to interact with the binding pocket of the monomeric N-cadherin unaltered, even when fluorescently labeled. Possible further derivatization of this sequence could be envisaged to further extend the potential of the designed retro-inverso peptide as diagnostic or theranostic agent for the oral route. Copyright © 2017. Published by Elsevier B.V.
A unified thermostat scheme for efficient configurational sampling for classical/quantum canonical ensembles via molecular dynamics
Jul 23, 2017   The Journal Of Chemical Physics
Zhang Z, Liu X, Chen Z, Zheng H, Yan K, Liu J
A unified thermostat scheme for efficient configurational sampling for classical/quantum canonical ensembles via molecular dynamics
Jul 23, 2017
The Journal Of Chemical Physics
We show a unified second-order scheme for constructing simple, robust, and accurate algorithms for typical thermostats for configurational sampling for the canonical ensemble. When Langevin dynamics is used, the scheme leads to the BAOAB algorithm that has been recently investigated. We show that the scheme is also useful for other types of thermostats, such as the Andersen thermostat and Nosé-Hoover chain, regardless of whether the thermostat is deterministic or stochastic. In addition to analytical analysis, two 1-dimensional models and three typical real molecular systems that range from the gas phase, clusters, to the condensed phase are used in numerical examples for demonstration. Accuracy may be increased by an order of magnitude for estimating coordinate-dependent properties in molecular dynamics (when the same time interval is used), irrespective of which type of thermostat is applied. The scheme is especially useful for path integral molecular dynamics because it consistently improves the efficiency for evaluating all thermodynamic properties for any type of thermostat.
6-OHDA Induces Oxidation of F-box Protein Fbw7β by Chaperone-Mediated Autophagy in Parkinson's Model
Jul 22, 2017   Molecular Neurobiology
Wang X, Zhai H, Wang F
6-OHDA Induces Oxidation of F-box Protein Fbw7β by Chaperone-Mediated Autophagy in Parkinson's Model
Jul 22, 2017
Molecular Neurobiology
Parkinson's disease (PD) is the most common movement disorder disease, and its pathological feature is the degenerative loss of dopaminergic neurons in the substantia nigra compacta (SNc). In this study, we investigated whether distinct stress conditions target F-box protein Fbw7β via converging mechanisms. Our results showed that the 6-hyroxydopamine (6-OHDA), which causes PD in animals' models, led to decreased stability of Fbw7β in DA neuronal SN4741 cells. Further experiments suggested that oxidized Fbw7β bound to heat-shock cognate protein 70 kDa, the key regulator for chaperone-mediated autophagy (CMA), at a higher affinity. Oxidative stress also increased the level of lysosomal-associated membrane protein 2A (LAMP2A), the rate-limiting receptor for CMA substrate flux, and stimulated CMA activity. These changes resulted in accelerated degradation of Fbw7β. 6-OHDA induced Fbw7β oxidation and increased LAMP2A in the SNc region of the mouse models. Consistently, the levels of oxidized Fbw7β were higher in postmortem PD brains compared with the controls. These findings for the first time revealed the specific mechanism of ubiquitin ligases, oxidative stress, and CMA-mediated protein degradation, to provide a new theoretical basis for further clarifying the mechanism of PD.
Influence of C-terminal truncation of murine Serum amyloid A on fibril structure
Jul 22, 2017   Scientific Reports
Rennegarbe M, Lenter I, Schierhorn A, Sawilla R, Haupt C
Influence of C-terminal truncation of murine Serum amyloid A on fibril structure
Jul 22, 2017
Scientific Reports
Amyloid A (AA) amyloidosis is a systemic protein misfolding disease affecting humans and other vertebrates. While the protein precursor in humans and mice is the acute-phase reactant serum amyloid A (SAA) 1.1, the deposited fibrils consist mainly of C-terminally truncated SAA fragments, termed AA proteins. For yet unknown reasons, phenotypic variations in the AA amyloid distribution pattern are clearly associated with specific AA proteins. Here we describe a bacterial expression system and chromatographic strategies to obtain significant amounts of C-terminally truncated fragments of murine SAA1.1 that correspond in truncation position to relevant pathological AA proteins found in humans. This enables us to investigate systematically structural features of derived fibrils. All fragments form fibrils under nearly physiological conditions that show similar morphological appearance and amyloid-like properties as evident from amyloid-specific dye binding, transmission electron microscopy and infrared spectroscopy. However, infrared spectroscopy suggests variations in the structural organization of the amyloid fibrils that might be derived from a modulating role of the C-terminus for the fibril structure. These results provide insights, which can help to get a better understanding of the molecular mechanisms underlying the different clinical phenotypes of AA amyloidosis.
Electronic Structure of Polyethylene: Role of Chemical, Morphological and Interfacial Complexity
Jul 22, 2017   Scientific Reports
Chen L, Huan TD, Ramprasad R
Electronic Structure of Polyethylene: Role of Chemical, Morphological and Interfacial Complexity
Jul 22, 2017
Scientific Reports
The electronic structure of an insulator encodes essential signatures of its short-term electrical performance and long-term reliability. A critical long-standing challenge though is that key features of the electronic structure of an insulator (and its evolution) under realistic conditions have not been entirely accessible, either via experimental or computational approaches, due to the inherent complexities involved. In this comprehensive study, we reveal the role of chemical and morphological imperfections that inevitably exist within the technologically important prototypical and pervasive insulator, polyethylene (PE), and at electrode/PE interfaces. Large-scale density functional theory computations and long-time molecular dynamics simulations were employed to accurately recover, explain and unravel a wide variety of experimental data obtained during the electrical degradation of PE. This scheme has allowed us to directly and realistically address the role of chemical, morphological and interfacial complexity in determining electronic structure. These efforts take us a step closer to understanding and potentially controlling dielectric degradation and breakdown.
Raman evidence for pressure-induced formation of diamondene
Jul 22, 2017   Nature Communications
Martins LGP, Matos MJS, Paschoal AR, Freire PTC, Andrade NF, Aguiar AL, Kong J, Neves BRA, de Oliveira AB, Mazzoni MSC, Filho AGS, Cançado LG
Raman evidence for pressure-induced formation of diamondene
Jul 22, 2017
Nature Communications
Despite the advanced stage of diamond thin-film technology, with applications ranging from superconductivity to biosensing, the realization of a stable and atomically thick two-dimensional diamond material, named here as diamondene, is still forthcoming. Adding to the outstanding properties of its bulk and thin-film counterparts, diamondene is predicted to be a ferromagnetic semiconductor with spin polarized bands. Here, we provide spectroscopic evidence for the formation of diamondene by performing Raman spectroscopy of double-layer graphene under high pressure. The results are explained in terms of a breakdown in the Kohn anomaly associated with the finite size of the remaining graphene sites surrounded by the diamondene matrix. Ab initio calculations and molecular dynamics simulations are employed to clarify the mechanism of diamondene formation, which requires two or more layers of graphene subjected to high pressures in the presence of specific chemical groups such as hydroxyl groups or hydrogens.The synthesis of two-dimensional diamond is the ultimate goal of diamond thin-film technology. Here, the authors perform Raman spectroscopy of bilayer graphene under pressure, and obtain spectroscopic evidence of formation of diamondene, an atomically thin form of diamond.
The exported chaperone Hsp70-x supports virulence functions for Plasmodium falciparum blood stage parasites
Jul 21, 2017   PloS One
Charnaud SC, Dixon MWA, Nie CQ, Chappell L, Sanders PR,   . . . . . .   , Rayner JC, Przyborski JM, Tilley L, Crabb BS, Gilson PR
The exported chaperone Hsp70-x supports virulence functions for Plasmodium falciparum blood stage parasites
Jul 21, 2017
PloS One
Malaria is caused by five different Plasmodium spp. in humans each of which modifies the host erythrocyte to survive and replicate. The two main causes of malaria, P. falciparum and P. vivax, differ in their ability to cause severe disease, mainly due to differences in the cytoadhesion of infected erythrocytes (IE) in the microvasculature. Cytoadhesion of P. falciparum in the brain leads to a large number of deaths each year and is a consequence of exported parasite proteins, some of which modify the erythrocyte cytoskeleton while others such as PfEMP1 project onto the erythrocyte surface where they bind to endothelial cells. Here we investigate the effects of knocking out an exported Hsp70-type chaperone termed Hsp70-x that is present in P. falciparum but not P. vivax. Although the growth of Δhsp70-x parasites was unaffected, the export of PfEMP1 cytoadherence proteins was delayed and Δhsp70-x IE had reduced adhesion. The Δhsp70-x IE were also more rigid than wild-type controls indicating changes in the way the parasites modified their host erythrocyte. To investigate the cause of this, transcriptional and translational changes in exported and chaperone proteins were monitored and some changes were observed. We propose that PfHsp70-x is not essential for survival in vitro, but may be required for the efficient export and functioning of some P. falciparum exported proteins.
O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking
Jul 21, 2017   The Journal Of Biological Chemistry
Takeuchi H, Yu H, Hao H, Takeuchi M, Ito A, Li H, Haltiwanger RS
O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking
Jul 21, 2017
The Journal Of Biological Chemistry
Glycosylation in the endoplasmic reticulum (ER) is closely associated with protein folding and quality control. We recently described a non-canonical ER quality control mechanism for folding of thrombospondin type 1 repeats by Protein O-fucosyltransferase 2 (POFUT2). Epidermal Growth Factor-like (EGF) repeats are also small, cysteine rich protein motifs that can be O-glycosylated by several ER-localized enzymes including Protein O-glucosyltransferase 1 (POGLUT1) and POFUT1. Both POGLUT1 and POFUT1 modify the Notch receptor on multiple EGF repeats and are essential for full Notch function. The fact that POGLUT1 and POFUT1 can distinguish between folded and unfolded EGF repeats raised the possibility that they participate in a quality control pathway for folding of EGF repeats in proteins such as Notch. Here we demonstrate that cell-surface expression of endogenous Notch1 in HEK293T cells is dependent on the presence of POGLUT1 and POFUT1 in an additive manner. In vitro unfolding assays reveal that addition of O-glucose or O-fucose stabilizes a single EGF repeat, and that addition of both O-glucose and O-fucose enhances stability in an additive manner. Finally, we solved the crystal structure of a single EGF repeat covalently modified by a full O-glucose trisaccharide at 2.2 Å resolution. The structure reveals that the glycan fills up a surface groove of the EGF with multiple contacts with the protein, providing a chemical basis for the stabilizing effects of the glycans. Taken together, this work suggests that O-fucose and O-glucose glycans cooperatively stabilize individual EGF repeats through intramolecular interactions, thereby regulating Notch trafficking in cells. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
Understanding Russell's viper venom factor V activator's substrate specificity by surface plasmon resonance and in-silico studies
Jul 21, 2017   PloS One
Yadav PK, Antonyraj CB, Basheer Ahamed SI, Srinivas S
Understanding Russell's viper venom factor V activator's substrate specificity by surface plasmon resonance and in-silico studies
Jul 21, 2017
PloS One
Blood coagulation factor V (FV) is activated either by Factor X or thrombin, cleaving at three different sites viz., Site I (Arg709-Ser710), site II (Arg1018-Thr1019), and site III (Arg1545-Ser1546). Russell's viper venom factor V activator (RVV-V) is a thrombin-like serine proteinase that activates FV with selective, single cleavage at site III. A long lasting effort is being pending in understanding the 'selective' binding specificity of the RVV-V towards site III. Here, we present the binding kinetic study of RVV-V with two designed peptides corresponding to the regions from site I (Gln699-Asn713) and site II (1008Lys-Pro1022), respectively, that include 15 amino acids. Our investigation for justifying the binding efficacy and kinetics of peptides includes SPR method, protein-peptide docking, molecular dynamics simulation, and principal component analysis (PCA). Surprisingly, the SPR experiment disclosed that the Peptide II showed a lower binding affinity with KD of 2.775 mM while the Peptide I showed none. Docking and simulation of both the peptides with RVV-V engaged either rooted or shallow binding for Peptide II and Peptide I respectively. The peptide binding resulted in global conformational changes in the native fold of RVV-V, whereas the similar studies for thrombin failed to make major changes in the native fold. In support, the PCA analysis for RVV-V showed the dislocation of catalytic triad upon binding both the peptides. Hence, RVV-V, a serine protease, is incompetent in cleaving these two sites. This study suggests a transition in RVV-V from the native rigid to the distorted flexible structure and paves a way to design a new peptide substrate/inhibitor.
Predicting Flory-Huggins χ from Simulations
Jul 21, 2017   Physical Review Letters
Zhang W, Gomez ED, Milner ST
Predicting Flory-Huggins χ from Simulations
Jul 21, 2017
Physical Review Letters
We introduce a method, based on a novel thermodynamic integration scheme, to extract the Flory-Huggins χ parameter as small as 10^{-3}kT for polymer blends from molecular dynamics (MD) simulations. We obtain χ for the archetypical coarse-grained model of nonpolar polymer blends: flexible bead-spring chains with different Lennard-Jones interactions between A and B monomers. Using these χ values and a lattice version of self-consistent field theory (SCFT), we predict the shape of planar interfaces for phase-separated binary blends. Our SCFT results agree with MD simulations, validating both the predicted χ values and our thermodynamic integration method. Combined with atomistic simulations, our method can be applied to predict χ for new polymers from their chemical structures.
Determining Potentials of Zero Charge of Metal Electrodes versus the Standard Hydrogen Electrode from Density-Functional-Theory-Based Molecular Dynamics
Jul 21, 2017   Physical Review Letters
Le J, Iannuzzi M, Cuesta A, Cheng J
Determining Potentials of Zero Charge of Metal Electrodes versus the Standard Hydrogen Electrode from Density-Functional-Theory-Based Molecular Dynamics
Jul 21, 2017
Physical Review Letters
We develop a computationally efficient scheme to determine the potentials of zero charge (PZC) of metal-water interfaces with respect to the standard hydrogen electrode. We calculate the PZC of Pt(111), Au(111), Pd(111) and Ag(111) at a good accuracy using this scheme. Moreover, we find that the interface dipole potentials are almost entirely caused by charge transfer from water to the surfaces, the magnitude of which depends on the bonding strength between water and the metals, while water orientation hardly contributes at the PZC conditions.
Drude Polarizable Force Field for Molecular Dynamics Simulations of Saturated and Unsaturated Zwitterionic Lipids
Jul 21, 2017   Journal Of Chemical Theory And Computation
Li H, Chowdhary J, Huang L, He X, MacKerell AD, Roux B
Drude Polarizable Force Field for Molecular Dynamics Simulations of Saturated and Unsaturated Zwitterionic Lipids
Jul 21, 2017
Journal Of Chemical Theory And Computation
Additive force fields are designed to account for induced electronic polarization in a mean-field average way using effective empirical fixed charges. The limitation of this approximation is cause for serious concerns, particularly in the case of lipid membranes, where the molecular environment undergoes dramatic variations over microscopic length scales. A polarizable force field based on the classical Drude oscillator offers a practical and computationally efficient framework for an improved representation of electrostatic interactions in molecular simulations. Building on the first-generation Drude polarizable force field for the dipalmitoylphosphatidylcholine 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) molecule, the present effort was undertaken to improve this initial model and expand the force field to a wider range of phospholipid molecules. New lipids parameterized include dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), and 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The iterative optimization protocol employed in this effort led to lipid models that achieve a good balance between reproducing quantum mechanical data on model compound representative of phospholipids and reproducing a range of experimental condensed phase properties of bilayers. A parameterization strategy based on a restrained ensemble - maximum entropy methodology was used to help accurately match the experimental NMR order parameters in the polar headgroup region. All the parameters were developed to be compatible with the remainder of the Drude polarizable force field that includes water, ions, proteins, DNA and selected carbohydrates.
Altering DNA-Programmable Colloidal Crystallization Paths by Modulating Particle Repulsion
Jul 21, 2017   Nano Letters
Wang MX, Brodin JD, Millan JA, Seo SE, Girard M, Olvera de la Cruz M, Lee B, Mirkin CA
Altering DNA-Programmable Colloidal Crystallization Paths by Modulating Particle Repulsion
Jul 21, 2017
Nano Letters
Colloidal crystal engineering with DNA can be used to realize precise control over nanoparticle (NP) arrangement. Here, we investigate a case of DNA-based assembly where the properties of DNA as a polyelectrolyte brush are employed to alter a hybridization-driven NP crystallization pathway. Using the coassembly of DNA-conjugated proteins and spherical gold nanoparticles (AuNPs) as a model system, we explore how steric repulsion between noncomplementary, neighboring NPs due to overlapping DNA shells can influence their ligand-directed behavior. Specifically, our experimental data coupled with coarse-grained molecular dynamics (MD) simulations reveal that, by changing factors related to NP repulsion, two structurally distinct outcomes can be achieved. When steric repulsion between DNA-AuNPs is significantly greater than that between DNA-proteins, a lower packing density crystal lattice is favored over the structure that is predicted by design rules based on DNA hybridization considerations alone. This is enabled by the large difference in DNA density on AuNPs versus proteins and can be tuned by modulating the flexibility, and thus conformational entropy, of the DNA on the constituent particles. At intermediate ligand flexibility, the crystallization pathways are energetically similar, and the structural outcome can be adjusted using the density of DNA duplexes on DNA-AuNPs and by screening the Coulomb potential between them. Such lattices are shown to undergo dynamic reorganization upon changing the salt concentration. These data help elucidate the structural considerations necessary for understanding repulsive forces in DNA-mediated assembly and lay the groundwork for using them to increase architectural diversity in engineering colloidal crystals.
Decreased levels of PDI and P5 in oligodendrocytes in Alzheimer's disease
Jul 21, 2017   Neuropathology : Official Journal Of The Japanese Society Of Neuropathology
Honjo Y, Ayaki T, Tomiyama T, Horibe T, Ito H, Mori H, Takahashi R, Kawakami K
Decreased levels of PDI and P5 in oligodendrocytes in Alzheimer's disease
Jul 21, 2017
Neuropathology : Official Journal Of The Japanese Society Of Neuropathology
Protein disulfide isomerase (PDI) is a chaperone protein located in the endoplasmic reticulum (ER). Nitric oxide-induced S-nitrosylation of PDI inhibits its enzymatic activity, leading to protein accumulation and activation of the unfolded protein response. Protein disulfide isomerase P5 (P5) is a member of the PDI family that mostly localizes to the ER lumen. Both S-nitrosylated PDI and S-nitrosylated P5 are found in Alzheimer's disease (AD) brain. Previously, we showed that expression of the ER stress marker, growth arrest, and DNA damage protein (GADD34) was significantly increased in neurons and oligodendrocytes in AD brain. In the present study, we showed that PDI and P5 levels were significantly decreased in oligodendrocytes in the brains of AD patients and an AD mouse model. Interestingly, these decreases were evident before the animals displayed typical AD pathology. Because we previously showed that small short interfering RNA knockdown of PDI or P5 could affect the viability of neuronal cells under ER stress, dysfunction of PDI and P5 under ER stress could cause apoptosis of neuronal cells. In summary, we showed that the levels of PDI and P5 were significantly decreased in the oligodendrocytes of AD patients. This phenomenon was also found in an AD mouse model before the animals displayed AD pathology. The overall findings suggest that oligodendrocytes may play important roles in AD pathogenesis. © 2017 Japanese Society of Neuropathology.
ER stress and the unfolded protein response in neurodegeneration
Jul 21, 2017   Nature Reviews. Neurology
Hetz C, Saxena S
ER stress and the unfolded protein response in neurodegeneration
Jul 21, 2017
Nature Reviews. Neurology
The clinical manifestation of neurodegenerative diseases is initiated by the selective alteration in the functionality of distinct neuronal populations. The pathology of many neurodegenerative diseases includes accumulation of misfolded proteins in the brain. In physiological conditions, the proteostasis network maintains normal protein folding, trafficking and degradation; alterations in this network - particularly disturbances to the function of endoplasmic reticulum (ER) - are thought to contribute to abnormal protein aggregation. ER stress triggers a signalling reaction known as the unfolded protein response (UPR), which induces adaptive programmes that improve protein folding and promote quality control mechanisms and degradative pathways or can activate apoptosis when damage is irreversible. In this Review, we discuss the latest advances in defining the functional contribution of ER stress to brain diseases, including novel evidence that relates the UPR to synaptic function, which has implications for cognition and memory. A complex concept is emerging wherein the consequences of ER stress can differ drastically depending on the disease context and the UPR signalling pathway that is altered. Strategies to target specific components of the UPR using small molecules and gene therapy are in development, and promise interesting avenues for future interventions to delay or stop neurodegeneration.
Protocols for Molecular Dynamics Simulations of RNA Nanostructures
Jul 21, 2017   Methods In Molecular Biology (Clifton, N.J.)
Kim T, Kasprzak WK, Shapiro BA
Protocols for Molecular Dynamics Simulations of RNA Nanostructures
Jul 21, 2017
Methods In Molecular Biology (Clifton, N.J.)
Molecular dynamics (MD) simulations have been used as one of the main research tools to study a wide range of biological systems and bridge the gap between X-ray crystallography or NMR structures and biological mechanism. In the field of RNA nanostructures, MD simulations have been used to fix steric clashes in computationally designed RNA nanostructures, characterize the dynamics, and investigate the interaction between RNA and other biomolecules such as delivery agents and membranes.In this chapter we present examples of computational protocols for molecular dynamics simulations in explicit and implicit solvent using the Amber Molecular Dynamics Package. We also show examples of post-simulation analysis steps and briefly mention selected tools beyond the Amber package. Limitations of the methods, tools, and protocols are also discussed. Most of the examples are illustrated for a small RNA duplex (helix), but the protocols are applicable to any nucleic acid structure, subject only to the computational speed and memory limitations of the hardware available to the user.
Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation
Jul 21, 2017   Frontiers In Cellular Neuroscience
Sun D, Gu G, Wang J, Chai Y, Fan Y, Yang M, Xu X, Gao W, Li F, Yin D, Zhou S, Chen X, Zhang J
Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation
Jul 21, 2017
Frontiers In Cellular Neuroscience
Traumatic brain injury (TBI) is one of the leading causes of trauma-induced mortality and disability, and emerging studies have shown that endoplasmic reticulum (ER) stress plays an important role in the pathophysiology of TBI. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been reported to act as an ER stress inhibitor and chemical chaperone and to have the potential to attenuate apoptosis and inflammation. To study the effects of TUDCA on brain injury, we subjected mice to TBI with a controlled cortical impact (CCI) device. Using western blotting, we first examined TBI-induced changes in the expression levels of GRP78, an ER stress marker, p-PERK, PERK, p-eIF2a, eIF2a, ATF4, p-Akt, Akt, Pten, Bax, Bcl-2, Caspase-12 and CHOP, as well as changes in the mRNA levels of Akt, GRP78, Caspase-12 and CHOP using RT-PCR. Neuronal cell death was assessed by a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and CHOP expression in neuronal cells was detected by double-immunofluorescence staining. Neurological and motor deficits were assessed by modified neurological severity scores (mNSS) and beam balance and beam walking tests, and brain water content was also assessed. Our results indicated that ER stress peaked at 72 h after TBI and that TUDCA abolished ER stress and inhibited p-PERK, p-eIF2a, ATF4, Pten, Caspase-12 and CHOP expression levels. Moreover, our results show that TUDCA also improved neurological function and alleviated brain oedema. Additionally, TUDCA increased p-Akt expression and the Bcl-2/Bax ratio. However, the administration of the Akt inhibitor MK2206 or siRNA targeting of Akt abolished the beneficial effects of TUDCA. Taken together, our results indicate that TUDCA may attenuate early brain injury via Akt pathway activation.
The relationship between folding and activity in UreG, an intrinsically disordered enzyme
Jul 21, 2017   Scientific Reports
Palombo M, Bonucci A, Etienne E, Ciurli S, Uversky VN, Guigliarelli B, Belle V, Mileo E, Zambelli B
The relationship between folding and activity in UreG, an intrinsically disordered enzyme
Jul 21, 2017
Scientific Reports
A growing body of literature on intrinsically disordered proteins (IDPs) led scientists to rethink the structure-function paradigm of protein folding. Enzymes are often considered an exception to the rule of intrinsic disorder (ID), believed to require a unique structure for catalysis. However, recent studies revealed the presence of disorder in several functional native enzymes. In the present work, we address the importance of dynamics for catalysis, by investigating the relationship between folding and activity in Sporosarcina pasteurii UreG (SpUreG), a P-loop GTPase and the first discovered native ID enzyme, involved in the maturation of the nickel-containing urease. The effect of denaturants and osmolytes on protein structure and activity was analyzed using circular dichroism (CD), Site-Directed Spin Labeling (SDSL) coupled to EPR spectroscopy, and enzymatic assays. Our data show that SpUreG needs a "flexibility window" to be catalytically competent, with both too low and too high mobility being detrimental for its activity.
A preliminary study on the effects of lanthanum (III) on plant vitronectin-like protein and its toxicological basis
Jul 24, 2017   Ecotoxicology And Environmental Safety
Wang L, He J, Yang Q, Li X, Wei H, Chen DDY, Huang X
A preliminary study on the effects of lanthanum (III) on plant vitronectin-like protein and its toxicological basis
Jul 24, 2017
Ecotoxicology And Environmental Safety
Vitronectin-like protein (VN) is widely found outside plant plasma membranes. The VN molecular surface contains a large number of active groups that combine strongly with rare earth elements (REEs), which means that VN is a preferential binding target for REEs exhibiting their toxic effects, but the toxicological mechanism remains unknown. This study used transmission electron microscopy, circular dichroism, fluorescence spectrometry, ultraviolet-visible spectroscopy, X-ray photoelectron spectroscopy, and calculational chemistry (homology modeling, molecular dynamics simulation and quantum chemical calculation) to preliminarily investigate the effect of lanthanum [La(III)] as an REE, on the structure of VN and its toxicological mechanism. The results showed that low-concentration La(III) could cause micro-interference to the VN molecular structure through weak interactions, such as electrostatic attraction. High-concentration La(III) formed stable complexes with VN, which changed the average binding energy and electron cloud density of VN, loosened the molecular structure and increased the disorder of VN molecule. The results of building a 3D model of VN and simulating the interaction between La(III) and VN using calculational chemistry showed that La(H2O)73+ in solution could coordinately bind to the carboxyl-/carbonyl-O groups in the negatively charged areas on the VN molecular surface. Furthermore, one or more strong H-bonds were formed to enhance the stability of the La(H2O)73+-VN complexes. In summary, low La(III) concentrations could cause micro-interference to the VN molecular structure, whereas high La(III) concentrations could coordinately bind to VN to form stable La-VN complexes, which destroyed the molecular structure of VN; thus the toxicological basis by which La(III) exhibits its toxic effects is its binding to VN. Copyright © 2017 Elsevier Inc. All rights reserved.

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