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Protein contact prediction

Paula V Monje, David Sant, Gaofeng Wang
This study comprehensively addresses the phenotype, function, and whole transcriptome of primary human and rodent Schwann cells (SCs) and highlights key species-specific features beyond the expected donor variability that account for the differential ability of human SCs to proliferate, differentiate, and interact with axons in vitro. Contrary to rat SCs, human SCs were insensitive to mitogenic factors other than neuregulin and presented phenotypic variants at various stages of differentiation, along with a mixture of proliferating and senescent cells, under optimal growth-promoting conditions...
January 11, 2018: Molecular Neurobiology
Caroline M Gorvin, Raghu Metpally, Victoria J Stokes, Fadil M Hannan, Sarath B Krishnamurthy, John D Overton, Jeffrey G Reid, Gerda E Breitwieser, Rajesh V Thakker
Mutations of the sigma subunit of the heterotetrameric adaptor-related protein complex 2 (AP2σ) impair signalling of the calcium-sensing receptor (CaSR), and cause familial hypocalciuric hypercalcaemia type 3 (FHH3). To date, FHH3-associated AP2σ mutations have only been identified at one residue, Arg15. We hypothesized that additional rare AP2σ variants may also be associated with altered CaSR function and hypercalcaemia, and sought for these by analysing >111,995 exomes (>60,706 from ExAc and dbSNP, and 51,289 from the Geisinger Health System-Regeneron DiscovEHR dataset which also contains clinical data)...
January 9, 2018: Human Molecular Genetics
Jiri Kozelka, Matus Durec, Radek Marek
In proteins, the indole side-chain of tryptophan can interact with water molecules either in-plane, forming H-bonds, or out-of-plane, with the water molecule contacting the aromatic pi-face. The latter interaction can be either of the lone-pair---pi (lp---pi) type or correspond to the O-H---pi binding mode, an ambiguity that X-ray structures usually do not resolve. Here we report molecular dynamics (MD) simulations of a solvated beta-galactosidase monomer which illustrate how a water molecule located at the pi-face of an indole side-chain of tryptophan can adapt to the position of proximate residues and "select" its binding mode...
January 9, 2018: Chemistry: a European Journal
Chongli Qin, Lucy J Colwell
Covariance analysis of protein sequence alignments uses coevolving pairs of sequence positions to predict features of protein structure and function. However, current methods ignore the phylogenetic relationships between sequences, potentially corrupting the identification of covarying positions. Here, we use random matrix theory to demonstrate the existence of a power law tail that distinguishes the spectrum of covariance caused by phylogeny from that caused by structural interactions. The power law is essentially independent of the phylogenetic tree topology, depending on just two parameters-the sequence length and the average branch length...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
Anna C Hughes, Sundharraman Subramanian, Charles E Dann, Daniel B Kearns
SwrA is the master activator of flagellar biosynthesis in Bacillus subtilis and SwrA activity is restricted by regulatory proteolysis in liquid environments. SwrA is proteolyzed by the LonA protease but requires a proteolytic adaptor protein, SmiA. Here we show that SwrA and SmiA interact directly. To better understand SwrA activity, SwrA was randomly mutagenized and loss-of-function and gain-of-function mutants were localized primarily to the predicted unstructured C-terminal region. Loss-of-function mutations impaired swarming motility and activation from the Pfla-che promoter...
January 8, 2018: Journal of Bacteriology
Marcello Maugeri-Saccà, Ruggero De Maria
The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway...
January 2, 2018: Pharmacology & Therapeutics
Lei Deng, Chao Fan, Zhiwen Zeng
BACKGROUND: Direct prediction of the three-dimensional (3D) structures of proteins from one-dimensional (1D) sequences is a challenging problem. Significant structural characteristics such as solvent accessibility and contact number are essential for deriving restrains in modeling protein folding and protein 3D structure. Thus, accurately predicting these features is a critical step for 3D protein structure building. RESULTS: In this study, we present DeepSacon, a computational method that can effectively predict protein solvent accessibility and contact number by using a deep neural network, which is built based on stacked autoencoder and a dropout method...
December 28, 2017: BMC Bioinformatics
Ryuta Shintakuya, Naru Kondo, Yoshiaki Murakami, Kenichiro Uemura, Naoya Nakagawa, Keisuke Okano, Shinya Takahashi, Taijiro Sueda
BACKGROUND: Although postoperative adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC) improves survival, its efficacy varies among individuals. Identification of biomarkers that can predict the efficacy of adjuvant chemotherapy for PDAC is essential. OBJECTIVES: To investigate the predictive value of secreted protein acidic and rich in cysteine (SPARC) expression in patients with PDAC treated with adjuvant gemcitabine in combination with S-1 (adjuvant GS) or adjuvant gemcitabine alone (adjuvant G alone)...
December 26, 2017: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
Darwin Yu Fu, Jens Meiler
Incorporating experimental restraints is a powerful method of increasing accuracy in computational protein small molecule docking simulations models. Different algorithms integrate distinct forms of biochemical data during the docking and/or scoring stages. These so-called hybrid methods make use of receptor-based information such as nuclear magnetic resonance (NMR) restraints or small molecule-based information such as structure-activity relationships (SAR). A third class of methods directly interrogates contacts between the protein receptor and the small molecule...
December 29, 2017: Journal of Chemical Information and Modeling
Yang Liu, Perry Palmedo, Qing Ye, Bonnie Berger, Jian Peng
While genes are defined by sequence, in biological systems a protein's function is largely determined by its three-dimensional structure. Evolutionary information embedded within multiple sequence alignments provides a rich source of data for inferring structural constraints on macromolecules. Still, many proteins of interest lack sufficient numbers of related sequences, leading to noisy, error-prone residue-residue contact predictions. Here we introduce DeepContact, a convolutional neural network (CNN)-based approach that discovers co-evolutionary motifs and leverages these patterns to enable accurate inference of contact probabilities, particularly when few related sequences are available...
December 19, 2017: Cell Systems
Floris J Van Eerden, Manuel N Melo, Pim W J M Frederix, Siewert J Marrink
The thylakoid membrane has a unique lipid composition, consisting mostly of galactolipids. These thylakoid lipids have important roles in photosynthesis. Here, we investigate to what extent these lipids bind specifically to the Photosystem II complex. To this end, we performed coarse-grain MD simulations of the Photosystem II complex embedded in a thylakoid membrane with realistic composition. Based on >85 μs simulation time, we find that monogalactosyldiacylglycerol and sulfoquinovosyldiacylglycerol lipids are enriched in the annular shell around the protein, and form distinct binding sites...
December 19, 2017: Biophysical Journal
Giorgio E Tamò, Luciano A Abriata, Giulia Fonti, Matteo Dal Peraro
Integrative modeling approaches attempt to combine experiments and computation to derive structure-function relationships in complex molecular assemblies. Despite their importance for the advancement of life sciences, benchmarking of existing methodologies is rather poor. The 12th round of the Critical Assessment of protein Structure Prediction (CASP) offered a unique niche to benchmark data and methods from two kinds of experiments often used in integrative modeling, namely residue-residue contacts obtained through crosslinking/mass-spectrometry (CLMS), and small-angle X-ray scattering (SAXS) experiments...
December 13, 2017: Proteins
Badri Adhikari, Jie Hou, Jianlin Cheng
Motivation: Significant improvements in the prediction of protein residue-residue contacts are observed in the recent years. These contacts, predicted using a variety of coevolution-based and machine learning methods, are the key contributors to the recent progress in ab initio protein structure prediction, as demonstrated in the recent CASP experiments. Continuing the development of new methods to reliably predict contact maps is essential to further improve ab initio structure prediction...
December 8, 2017: Bioinformatics
John D McCorvy, Kyle V Butler, Brendan Kelly, Katie Rechsteiner, Joel Karpiak, Robin M Betz, Bethany L Kormos, Brian K Shoichet, Ron O Dror, Jian Jin, Bryan L Roth
Development of biased ligands targeting G protein-coupled receptors (GPCRs) is a promising approach for current drug discovery. Although structure-based drug design of biased agonists remains challenging even with an abundance of GPCR crystal structures, we present an approach for translating GPCR structural data into β-arrestin-biased ligands for aminergic GPCRs. We identified specific amino acid-ligand contacts at transmembrane helix 5 (TM5) and extracellular loop 2 (EL2) responsible for Gi/o and β-arrestin signaling, respectively, and targeted those residues to develop biased ligands...
December 11, 2017: Nature Chemical Biology
Pintu Patra, Christopher N Vassallo, Daniel Wall, Oleg A Igoshin
Swarming bacteria use kin discrimination to preferentially associate with their clonemates for certain cooperative behaviors. Kin discrimination can manifest as an apparent demarcation line (a region lacking cells or with much lower cell density) between antagonist strains swarming toward each other. In contrast, two identical strains merge with no demarcation. Experimental studies suggest contact-dependent killing between different strains as a mechanism of kin discrimination, but it is not clear whether this killing is sufficient to explain the observed patterns...
December 5, 2017: Biophysical Journal
Zhipeng Yu, Sijia Wu, Wenzhu Zhao, Long Ding, David Shiuan, Feng Chen, Jianrong Li, Jingbo Liu
The objective of this work was to identify a novel ACE inhibitory peptide from myosin using a number of in silico methods. Myosin was evaluated as a substrate for use in the generation of ACE inhibitory peptides using BIOPEP and ExPASy PeptideCutter. Then the ACE inhibitory activity prediction of peptides in silico was evaluated using the program peptide ranker, following the database search of known and unknown peptides using the program BIOPEP. In addition, the interaction mechanisms of the peptide and ACE were evaluated by DS...
December 6, 2017: Food & Function
Varun Mandalaparthy, Venkata Ramana Sanaboyana, Hitesh Rafalia, Shachi Gosavi
One of the main barriers to accurate computational protein structure prediction is searching the vast space of protein conformations. Distance restraints or inter-residue contacts have been used to reduce this search space, easing the discovery of the correct folded state. It has been suggested that about one contact for every twelve residues may be sufficient to predict structure at fold level accuracy. Here, we use coarse-grained structure-based models in conjunction with molecular dynamics simulations to examine this empirical prediction...
December 3, 2017: Proteins
Yoshinobu Kato, Kazuhiko Sugimoto, Toshiharu Shikanai
The chloroplast NADH dehydrogenase-like (NDH) complex is structurally similar to respiratory complex I and mediates photosystem I (PSI) cyclic electron flow. In Arabidopsis, chloroplast NDH is composed of at least 29 subunits and associates with two copies of PSI to form the NDH-PSI supercomplex. Here, we found that CHLORORESPIRATORY REDUCTION 3 (CRR3) is an assembly factor required for the accumulation of subcomplex B (SubB) of chloroplast NDH. In sucrose density gradient centrifugation, CRR3 was detected in three protein complexes...
December 4, 2017: Plant Physiology
Paul Labute
We present a number of techniques to analyze protein-ligand interactions in the context of medicinal chemistry: crystal Contract Preferences, Electrostatic Maps and pharmacophore screening using Hückel Theory. Contact Preferences is a statistical technique to predict hydrophobic and hydrophilic geometry in receptor active sites. Electrostatic Maps use the Poisson-Boltzmann Equation to model solvation effects and are particularly useful for predicting hydrophobic regions. Pharmacophore annotation with Hückel Theory provides finer detail of hydrogen bonding interactions, including CH...
2018: Methods in Molecular Biology
Ignacio M Larrayoz, Hilda Ferrero, Eva Martisova, Francisco J Gil-Bea, María J Ramírez, Alfredo Martínez
Memory decline is common in elderly individuals and is the hallmark of Alzheimer's disease (AD). Memory failure follows the loss of synaptic contacts in the cerebral cortex and hippocampus, caused in part by cytoskeleton disruption. Adrenomedullin (AM) and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), are microtubule-associated proteins (MAP) whose expression has been identified as a potential biomarker for predicting progression from predementia to clinical AD. Here we analyze the connection between AM levels and memory preservation...
2017: Frontiers in Molecular Neuroscience
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