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Rui Zhang, Kenneth S Schweizer
The Elastically Collective Nonlinear Langevin Equation theory for one-component viscous liquids and suspensions is generalized to treat coupled slow activated relaxation and diffusion in glass-forming binary sphere mixtures of any composition, size ratio and inter-particle interactions. A trajectory-level dynamical coupling parameter concept is introduced to construct two coupled dynamic free energy functions for the smaller penetrant and larger matrix particle. A two-step dynamical picture is proposed where the first step process involves matrix-facilitated penetrant hopping quantified in a self-consistent manner based on a temporal coincidence condition...
January 18, 2018: Journal of Physical Chemistry. B
Yufei Yue, Yue Ma, Ping Qian, Hong Guo
Ubiquitin-like (UBL) protein modifications play a key role in regulating protein function. In contrast to the ubiquitin (UB) and small ubiquitin-like modifier (SUMO) which are ligated to a massive segment of proteome, the UBL NEDD8 is highly selective for modifying a lysine residue on closely related cullin proteins (CULs). In this study, the X-ray structure of a trapped E3-E2~NEDD8-target intermediate (RBX1-UBC1~NEDD8-CUL1-DCN1) is used to build computer models, and combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) and free energy (potential of mean force) simulations are performed to investigate the catalytic mechanism of the NEDD8 transfer from E2 to the lysine residue (K720) on the substrate in the complex...
January 18, 2018: Journal of Chemical Information and Modeling
Yasmin Shamsudin Khan, Hugo Gutiérrez de Terán, Johan Åqvist
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) 1 and 2 with varying degrees of selectivity. A group of COX-2 selective inhibitors - coxibs - bind in a time-dependent manner through a three-step mechanism, utilizing a side-pocket in the binding site. Coxibs have been extensively probed to identify the structural features regulating the slow tight-binding mechanism responsible for COX-2 selectivity. In this study, we further probe a structurally and kinetically diverse data set of COX inhibitors in COX-2 by molecular dynamics and free energy simulations...
January 18, 2018: Biochemistry
Parthiban Marimuthu, Kalaimathy Singaravelu
Myeloid cell leukemia 1 (Mcl1) is an anti-apoptotic protein that plays central role in apoptosis regulation. Also, Mcl1 has the potency to resist apoptotic cues resulting in up-regulation and cancer cell protection. A molecular probe that has the potential to specifically target Mcl1, and thereby provoke its down-regulatory activity is very essential. The aim of the current study is to probe the internal conformational dynamics of protein motions and potential binding mechanism in response to a series of picomolar range Mcl1 inhibitors using explicit-solvent molecular dynamics (MD) simulations...
January 18, 2018: Biochemistry
Yuko Nagura, Akimasa Tsujimoto, Wayne W Barkmeier, Hidehiko Watanabe, William W Johnson, Toshiki Takamizawa, Mark A Latta, Masashi Miyazaki
The relationship between enamel bond fatigue durability and surface free-energy characteristics with universal adhesives was investigated. The initial shear bond strengths and shear fatigue strengths of five universal adhesives to enamel were determined with and without phosphoric acid pre-etching. The surface free-energy characteristics of adhesive-treated enamel with and without pre-etching were also determined. The initial shear bond strength and shear fatigue strength of universal adhesive to pre-etched enamel were higher than those to ground enamel...
January 18, 2018: European Journal of Oral Sciences
Bharati Pandey, Sonam Grover, Sukriti Goyal, Anchala Kumari, Aditi Singh, Salma Jamal, Jagdeep Kaur, Abhinav Grover
The enzyme Pantothenate synthetase (PS) represents a potential drug target in Mycobacterium tuberculosis. Its X-ray crystallographic structure has demonstrated the significance and importance of conserved active site residues including His44, His47, Asn69, Gln72, Lys160 and Gln164 in substrate binding and formation of pantoyl adenylate intermediate. In the current study, molecular mechanism of decreased affinity of the enzyme for ATP caused by alanine mutations was investigated using molecular dynamics (MD) simulations and free energy calculations...
January 17, 2018: Scientific Reports
V V Hemanth Giri Rao, Shachi Gosavi
For successful protease inhibition, the reactive center loop (RCL) of the two-domain serine protease inhibitor, α1-antitrypsin (α1-AT), needs to remain exposed in a metastable active conformation. The α1-AT RCL is sequestered in a β-sheet in the stable latent conformation. Thus, to be functional, α1-AT must always fold to a metastable conformation while avoiding folding to a stable conformation. We explore the structural basis of this choice using folding simulations of coarse-grained structure-based models of the two α1-AT conformations...
January 17, 2018: Proceedings of the National Academy of Sciences of the United States of America
Michael Kirchhoff, Thomas Parr, Ensor Palacios, Karl Friston, Julian Kiverstein
This work addresses the autonomous organization of biological systems. It does so by considering the boundaries of biological systems, from individual cells to Home sapiens, in terms of the presence of Markov blankets under the active inference scheme-a corollary of the free energy principle. A Markov blanket defines the boundaries of a system in a statistical sense. Here we consider how a collective of Markov blankets can self-assemble into a global system that itself has a Markov blanket; thereby providing an illustration of how autonomous systems can be understood as having layers of nested and self-sustaining boundaries...
January 2018: Journal of the Royal Society, Interface
Subhajit Roy, Bawneet K Narang, Manish K Gupta, Vikrant Abbot, Virender Singh, Ravindra K Rawal
Flexible docking simulations were carried out on a series of isocytosine analogs as xanthine oxidase (XO) inhibitors. This was done by analysing the interaction of these compounds at the active site of XO. The binding free energies of the analogs were calculated using GoldScore. The binding modes of the best-fit conformation were studied, providing some handy important interactions. The results obtained henceforth provided an insight into the pharmacophoric structural requirements for XO inhibition for this class of molecules...
January 17, 2018: Drug Research
A I Smirnov, T A Soldatov, O A Petrenko, A Takata, T Kida, M Hagiwara, A Ya Shapiro, M E Zhitomirsky
We observe a disappearance of the 1/3 magnetization plateau and a striking change of the magnetic configuration under a moderate doping of the model triangular antiferromagnet RbFe(MoO_{4})_{2}. The reason is an effective lifting of degeneracy of mean-field ground states by a random potential of impurities, which compensates, in the low-temperature limit, the fluctuation contribution to free energy. These results provide a direct experimental confirmation of the fluctuation origin of the ground state in a real frustrated system...
July 28, 2017: Physical Review Letters
Simon Groth, Tobias Dornheim, Travis Sjostrom, Fionn D Malone, W M C Foulkes, Michael Bonitz
In a recent Letter [T. Dornheim et al., Phys. Rev. Lett. 117, 156403 (2016)PRLTAO0031-900710.1103/PhysRevLett.117.156403], we presented the first quantum Monte Carlo (QMC) results for the warm dense electron gas in the thermodynamic limit. However, a complete parametrization of the exchange-correlation free energy with respect to density, temperature, and spin polarization remained out of reach due to the absence of (i) accurate QMC results below θ=k_{B}T/E_{F}=0.5 and (ii) QMC results for spin polarizations different from the paramagnetic case...
September 29, 2017: Physical Review Letters
Nikolay A Simakov, Maria G Kurnikova
The dependency of current-voltage characteristics of the α-hemolysin channel on the channel position within the membrane was studied using Poisson-Nernst-Planck theory of ion conductivity with soft repulsion between mobile ions and protein atoms (SP-PNP). The presence of the membrane environment also influences the protonation state of the residues at the boundary of the water-lipid interface. In this work, we predict that Asp and Lys residues at the protein rim change their protonation state upon penetration to the lipid environment...
January 16, 2018: Journal of Membrane Biology
Yu Wen, Dehong Xia
The purpose of this study is to provide scientific guidance for morphological control of nanoparticle synthesis by gas phase method. A universal thermodynamics model is developed to predict morphology of nanoparticles fabricated by inert gas condensation method. By the use of the model, morphologies of aluminum nanocrystals are predicted under various preparation conditions. There are two kinds of energies that determine the formation of nanoparticles morphology jointly, which are Gibbs free energy for nanoparticles and energy variation during the process...
January 17, 2018: Nanotechnology
Esteban M Schenfeld, Sergio R Ribone, Mario A Quevedo
Despite its vastly demonstrated clinical efficacy, zidovudine (AZT) exhibits several suboptimal pharmacokinetic properties. In particular, its short plasmatic half-life (t1/2 ~ 1 h) is related to its low bound fraction to whole plasmatic proteins and in particular to human serum albumin (HSA). The design of prodrugs constitutes a promising strategy to enhance AZT pharmacokinetic properties, including its affinity for HSA. Recently, we reported the synthesis and chemical stability evaluation of three novel prodrugs of AZT obtained by derivatization with dicarboxylic acids (1-3)...
January 12, 2018: European Journal of Pharmaceutical Sciences
Ali El-Lakkani, Eman M Ibrahim
The function of a particular RNA molecule within an organic system is principally determined by its structure. The current physical methods available for structure determination are time consuming and expensive. Hence, computational methods for structure prediction are often used. The prediction of the structure of a large single sequence of RNA needs a lot of research work. In the present work, a method is introduced to improve the prediction of large single sequence RNA secondary structure obtained by Mfold program using the concept of minimum free energy...
January 12, 2018: Biochemical and Biophysical Research Communications
Attilio Vittorio Vargiu, Venkata Krishnan Ramaswamy, Ivana Malvacio, Giuliano Malloci, Ulrich Kleinekathöfer, Paolo Ruggerone
BACKGROUND: Efflux pumps of the Resistance-Nodulation-cell Division superfamily confer multi-drug resistance to Gram-negative bacteria. The most-studied polyspecific transporter belonging to this class is the inner-membrane trimeric antiporter AcrB of Escherichia coli. In previous studies, a functional rotation mechanism was proposed for its functioning, according to which the three monomers undergo concerted conformational changes facilitating the extrusion of substrates. However, the molecular determinants and the energetics of this mechanism still remain unknown, so its feasibility must be proven mechanistically...
January 12, 2018: Biochimica et Biophysica Acta
Mithun Biswas, Benjamin Lickert, Gerhard Stock
Enhanced sampling techniques represent a versatile approach to account for rare conformational transitions in biomolecules. A particularly promising strategy is to combine massive parallel computing of short molecular dynamics (MD) trajectories (to sample the free energy landscape of the system) with Markov state modeling (to rebuild the kinetics from the sampled data). To obtain well-distributed initial structures for the short trajectories, it is proposed to employ Metadynamics MD, which quickly sweeps through the entire free energy landscape of interest...
January 16, 2018: Journal of Physical Chemistry. B
Yun Chul Woo, Youngjin Kim, Minwei Yao, Leonard Demegilio Tijing, Juneseok Choi, Sangho Lee, Seunghyun Kim, Hokyong Shon
In this study, composite membranes were fabricated via layer-by-layer (LBL) assembly of negatively-charged silica aerogel (SiA) and 1H, 1H, 2H, 2H - Perfluorodecyltriethoxysilane (FTCS) on a polyvinylidene fluoride phase inversion membrane, and interconnecting them with positively-charged poly(diallyldimethylammonium chloride) (PDDA) via electrostatic interaction. The results showed that the PDDA-SiA-FTCS coated membrane had significantly enhanced the membrane structure and properties. New trifluoromethyl and tetrafluoroethylene bonds appeared at the surface of the coated membrane, which led to lower surface free energy of the composite membrane...
January 16, 2018: Environmental Science & Technology
Gyan P Johari
With the objective of increasing the bioavailability of poorly soluble curative compounds, we describe a thermodynamics-based method for increasing their solubility, σ. It requires forming their pressure-densified glassy (PDG) state by supercooling the melt under a high pressure to form glass, depressurizing, and recovering the glass at a low temperature. First, we formally show that the excess free energy of PDG is higher at ambient pressure than that of a glass (normally) formed by supercooling the melt at ambient pressure (NG), and therefore their σ will be higher...
January 16, 2018: Journal of Physical Chemistry. B
N Lokesh, Andreas Seegerer, Johnny Hioe, Ruth M Gschwind
The low sensitivity of NMR and transient key intermediates below detection limit are the central problems studying reaction mechanisms by NMR. Sensitivity can be enhanced by hyperpolarization techniques such as dynamic nuclear polarization or the incorporation/interaction of special hyperpolarized molecules. However, all of these techniques require special equipment, are restricted to selective reactions or undesirably influence the reaction pathways. Here, we apply the Chemical Exchange Saturation Transfer (CEST) technique for the first time to NMR detect and characterize previously unobserved transient reaction intermediates in organocatalysis...
January 16, 2018: Journal of the American Chemical Society
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