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Ivan Yu Chernyshov, Philip V Toukach
Motivation: Glycans and glycoconjugates are usually recorded in dedicated databases in residue-based notations. Only a few of them can be converted into chemical (atom-based) formats highly demanded in conformational and biochemical studies. In this work, we present a tool for translation from a residue-based glycan notation to SMILES. Results: The REStLESS algorithm for translation from the CSDB Linear notation to SMILES was developed. REStLESS stands for ResiduEs as Smiles and LinkagEs as SmartS, where SMARTS reaction expressions are used to merge pre-encoded residues into a molecule...
March 14, 2018: Bioinformatics
Deepak Reddy Gade, Amareswararao Makkapati, Rajesh Babu Yarlagadda, Godefridus J Peters, B S Sastry, V V S Rajendra Prasad
Overexpression of P-glycoprotein (P-gp) leads to the emergence of multidrug resistance (MDR) in cancer treatment. Acridones have the potential to reverse MDR and sensitize cells. In the present study, we aimed to elucidate the chemosensitization potential of acridones by employing various molecular modelling techniques. Pharmacophore modeling was performed for the dataset of chemosensitizing acridones earlier proved for cytotoxic activity against MCF7 breast cancer cell line. Gaussian-based QSAR studies also performed to predict the favored and disfavored region of the acridone molecules...
February 24, 2018: Computational Biology and Chemistry
Hendrik Göddeke, M Hadi Timachi, Cedric A Hutter, Laura Galazzo, Markus A Seeger, Mikko Karttunen, Enrica Bordignon, Lars V Schäfer
ATP-binding cassette (ABC) transporters are ATP-driven molecular machines, in which ATP binding and hydrolysis in the nucleotide-binding domains (NBDs) is chemo-mechanically coupled to large-scale, alternating access conformational changes in the transmembrane domains (TMDs), ultimately leading to the translocation of substrates across biological membranes. The precise nature of the structural dynamics behind the large-scale conformational transition as well as the coupling of NBD and TMD motions is still unresolved...
March 16, 2018: Journal of the American Chemical Society
Alberto Perez, Florian Sittel, Gerhard Stock, Ken A Dill
The molecular actions of proteins occur along reaction coordinates. Current computer methods have limited ability to explore them. We describe a fast protocol called MELD-path that: (1) efficiently samples relevant conformational states via MELD, an accelerator of Molecular Dynamics (MD), (2) seeds multiple short MD trajectories from MELD states, then (3) constructs Markov State Models (MSM) that give the routes and kinetics. We tested the method against extensive (multi μs) MD simulations of the right-handed- to left-handed-helix transition of a 9-mer peptide of AIB, the symmetry of which allows us to establish convergence...
March 16, 2018: Journal of Chemical Theory and Computation
Manus Carey, Emily Donaldson, Antonio J Signes-Pastor, Andrew A Meharg
There has been an increasing realisation that young infants are exposed to elevated concentrations of the carcinogen inorganic arsenic, relative to adults. This is because many infant food products are rice based, and rice is ~10-fold elevated in inorganic arsenic compared to most other foods. The European Commission (EC) has acted on this concern setting stricter standards for infants, 100 μg of inorganic arsenic per kg of food (100 μg/kg), as compared to adults (200 μg/kg), for rice based foods, a law that was brought into place in 1st January 2016...
2018: PloS One
Xiangying Guan, Alok Upadhyay, Sudipto Munshi, Raj Chakrabarti
Across all families of enzymes, only a dozen or so distinct classes of non-natural small molecule activators have been characterized, with only four known modes of activation among them. All of these modes of activation rely on naturally evolved binding sites that trigger global conformational changes. Among the enzymes that are of greatest interest for small molecule activation are the seven sirtuin enzymes, nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play a central role in the regulation of healthspan and lifespan in organisms ranging from yeast to mammals...
2018: PloS One
Zanxia Cao, Yunqiang Bian, Guodong Hu, Liling Zhao, Zhenzhen Kong, Yuedong Yang, Jihua Wang, Yaoqi Zhou
Thermodynamics of the permeation of amino acids from water to lipid bilayers is an important first step for understanding the mechanism of cell-permeating peptides and the thermodynamics of membrane protein structure and stability. In this work, we employed bias-exchange metadynamics simulations to simulate the membrane permeation of all 20 amino acids from water to the center of a dipalmitoylphosphatidylcholine (DPPC) membrane (consists of 256 lipids) by using both directional and torsion angles for conformational sampling...
March 16, 2018: International Journal of Molecular Sciences
Sweet Ping Ng, Joseph M Herman
Pancreatic cancer is a devastating disease with poor survival outcomes. Recent studies have shown that the addition of radiotherapy to chemotherapy in the setting of locally advanced pancreatic cancer did not improve overall survival outcome. These studies commonly utilize conventional radiotherapy treatment fractionation and technique (typically 3-D conformal radiotherapy or intensity modulated radiotherapy). Although no clear benefit in overall survival was demonstrated in those studies, those who received radiotherapy did have a clear benefit in terms of local control...
March 16, 2018: Cancers
Bartłomiej Czech, Lampros Lamprou, Samuel McCandlish, James Sully
The Berry connection describes transformations induced by adiabatically varying Hamiltonians. We study how zero modes of the modular Hamiltonian are affected by varying the region that supplies the modular Hamiltonian. In the vacuum of a 2D conformal field theory, global conformal symmetry singles out a unique modular Berry connection, which we compute directly and in the dual three-dimensional anti-de Sitter (AdS_{3}) picture. In certain cases, Wilson loops of the modular Berry connection compute lengths of curves in AdS_{3}, reproducing the differential entropy formula...
March 2, 2018: Physical Review Letters
Diego Jaramillo-Cano, Maud Formanek, Christos N Likos, Manuel Camargo
Star block-copolymers (SBCs) have been demonstrated to constitute self-assembling building blocks with specific softness, functionalization, shape and flexibility. In this work we study the behaviour of an isolated SBC under shear flow by means of particle-based multi-scale simulations. We systematically analyse the conformational properties of low-functionality stars as well as the formation of attractive patches on their corona as a function of the shear rate. We cover a wide range of system parameters, including functionality, amphiphilicity and solvent quality...
March 16, 2018: Journal of Physical Chemistry. B
Michael K Krapf, Jennifer Gallus, Sahel Vahdati, Michael Wiese
Multidrug resistance occurring during cancer chemotherapy is a major obstacle for effectiveness and response to therapy and is often caused by ATP-binding cassette (ABC) efflux transporters. Belonging to the family of ABC transporters, breast cancer resistance protein is getting more and more in the spotlight of research. As a strategy to overcome multidrug resistance, inhibitors of ABC transporters were synthesized, which could be applied in combination with cytostatic drugs. For this purpose, 2,4-disubstituted pyridopyrimidine derivatives were synthesized...
March 16, 2018: Journal of Medicinal Chemistry
Nicolas Daffern, Zhonglei Chen, Yongbo Zhang, Leslie Pick, Ishwar Radhakrishnan
The ligand-binding domains (LBD) of the NR5A subfamily of nuclear receptors activate transcription via ligand-dependent and ligand-independent mechanisms. The Drosophila Ftz-F1 receptor (NR5A3) belongs to the latter category and its ligand-independence is attributed to a short helical segment (6) within the protein that resides in the canonical ligand-binding pocket (LBP) in the crystalline state. Here, we show that the 6 helix is dynamic in solution when Ftz-F1 is bound to the LxxLL motif of its cofactor Ftz, undergoing motions on the fast (picosecond-nanosecond) as well as slow (microsecond-millisecond) timescales...
March 16, 2018: Biochemistry
Sunandan Mukherjee, Chandran Nithin, Yasaswi Divakaruni, Ranjit Prasad Bahadur
We dissect the protein-protein interfaces into water preservation (WP), water hydration (WH) and water dehydration (WD) sites by comparing the water mediated hydrogen bonds (H-bond) in the bound and unbound states of the interacting subunits. Upon subunit complexation, if a H-bond between an interface water and a protein polar group is retained, we assign it as WP site; if it is lost, we assign it as WD site and if a new H-bond is created, we assign it as WH site. We find that the density of WD sites is highest followed by WH and WP sites except in antigen and (or) antibody complexes, where the density of WH sites is highest followed by WD and WP sites...
March 16, 2018: Journal of Biomolecular Structure & Dynamics
Jeiwan Tan, Wooseok Yang, Yunjung Oh, Hyungsoo Lee, Jaemin Park, Jooho Moon
Amorphous molybdenum sulfide (a-MoSx) is a promising hydrogen evolution catalyst owing to its low cost and high activity. A simple electrodeposition method (cyclic voltammetry) allows uniform formation of a-MoSx films on conductive surfaces. However, the morphology of a-MoSx, deposited on a TiO2/Sb2Se3 photocathode could be modulated by varying the starting potential. The cathodically initiated a-MoSx showed conformal film-like morphology, while anodic initiation induced inhomogeneous particulate deposition...
March 16, 2018: ACS Applied Materials & Interfaces
Chuanhui Liao, Jin Hong, Dingtao Zhao, Shuang Zhang, Changhong Chen
Food waste is a worldwide problem due to its effects on carbon emission, water pollution, and arable lands. Previous studies of food waste generation and reduction focus on demographic, psychological, and situational factors, whereas the effects of culture in different countries have been ignored. This paper investigates the influence of Confucian culture on behaviors that waste food, considering additional factors of face saving and group conformity. We used an integrated behavioral intention model combining the TPB model and Lee's modified Fishbein model...
March 15, 2018: Environmental Science and Pollution Research International
Angelica Nakagawa Lima, Ronaldo Junio de Oliveira, Antônio Sérgio Kimus Braz, Maurício Garcia de Souza Costa, David Perahia, Luis Paulo Barbour Scott
There are two different prion conformations: (1) the cellular natural (PrPC ) and (2) the scrapie (PrPSc ), an infectious form that tends to aggregate under specific conditions. PrPC and PrPSc are widely different regarding secondary and tertiary structures. PrPSc contains more and longer β-strands compared to PrPC . The lack of solved PrPSc structures precludes a proper understanding of the mechanisms related to the transition between cellular and scrapie forms, as well as the aggregation process. In order to investigate the conformational transition between PrPC and PrPSc , we applied MDeNM (molecular dynamics with excited normal modes), an enhanced sampling simulation technique that has been recently developed to probe large structural changes...
March 15, 2018: European Biophysics Journal: EBJ
Ariel Talavera, Jelle Hendrix, Wim Versées, Dukas Jurėnas, Katleen Van Nerom, Niels Vandenberk, Ranjan Kumar Singh, Albert Konijnenberg, Steven De Gieter, Daniel Castro-Roa, Anders Barth, Henri De Greve, Frank Sobott, Johan Hofkens, Nikolay Zenkin, Remy Loris, Abel Garcia-Pino
Bacterial protein synthesis is intricately connected to metabolic rate. One of the ways in which bacteria respond to environmental stress is through posttranslational modifications of translation factors. Translation elongation factor Tu (EF-Tu) is methylated and phosphorylated in response to nutrient starvation upon entering stationary phase, and its phosphorylation is a crucial step in the pathway toward sporulation. We analyze how phosphorylation leads to inactivation of Escherichia coli EF-Tu. We provide structural and biophysical evidence that phosphorylation of EF-Tu at T382 acts as an efficient switch that turns off protein synthesis by decoupling nucleotide binding from the EF-Tu conformational cycle...
March 2018: Science Advances
Jeliazko R Jeliazkov, Adnan Sljoka, Daisuke Kuroda, Nobuyuki Tsuchimura, Naoki Katoh, Kouhei Tsumoto, Jeffrey J Gray
Antibodies can rapidly evolve in specific response to antigens. Affinity maturation drives this evolution through cycles of mutation and selection leading to enhanced antibody specificity and affinity. Elucidating the biophysical mechanisms that underlie affinity maturation is fundamental to understanding B-cell immunity. An emergent hypothesis is that affinity maturation reduces the conformational flexibility of the antibody's antigen-binding paratope to minimize entropic losses incurred upon binding. In recent years, computational and experimental approaches have tested this hypothesis on a small number of antibodies, often observing a decrease in the flexibility of the complementarity determining region (CDR) loops that typically comprise the paratope and in particular the CDR-H3 loop, which contributes a plurality of antigen contacts...
2018: Frontiers in Immunology
Qianqian Wang, Jiahui Xu, Ying Li, Jumin Huang, Zebo Jiang, Yuwei Wang, Liang Liu, Elaine Lai Han Leung, Xiaojun Yao
Protein arginine methyltransferase 5 (PRMT5) is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis. Many efforts have been taken in discovering small-molecular inhibitors against PRMT5, but very few were reported and most of them were SAM-competitive. EPZ015666 is a recently reported PRMT5 inhibitor with a new binding site, which is different from S-adenosylmethionine (SAM)-binding pocket. This new binding site provides a new clue for the design and discovery of potent and specific PRMT5 inhibitors...
2018: Frontiers in Pharmacology
Tiffany A Thibaudeau, Raymond T Anderson, David M Smith
Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin-proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer's, Parkinson's, and Huntington's disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates...
March 15, 2018: Nature Communications
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