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J C Gaines, S Acebes, A Virrueta, M Butler, L Regan, C S O'Hern
We compare side chain prediction and packing of core and non-core regions of soluble proteins, protein-protein interfaces, and transmembrane proteins. We first identified or created comparable databases of high-resolution crystal structures of these three protein classes. We show that the solvent-inaccessible cores of the three classes of proteins are equally densely packed. As a result, the side chains of core residues at protein-protein interfaces and in the membrane-exposed regions of transmembrane proteins can be predicted by the hard-sphere plus stereochemical constraint model with the same high prediction accuracies (> 90%) as core residues in soluble proteins...
February 10, 2018: Proteins
Oliver Buß, Patrick C F Buchholz, Maike Gräff, Peter Klausmann, Jens Rudat, Jürgen Pleiss
The ω-Transaminase Engineering Database (oTAED) was established as a publicly accessible resource on sequences and structures of the biotechnologically relevant ω-transaminases (ω-TAs) from Fold types I and IV. The oTAED integrates sequence and structure data, provides a classification based on fold type and sequence similarity, and applies a standard numbering scheme to identify equivalent positions in homologous proteins. The oTAED includes 67210 proteins (114655 sequences) which are divided into 169 homologous families based on global sequence similarity...
February 8, 2018: Proteins
Mara Kozic, Stephen J Fox, Jens M Thomas, Chandra S Verma, Daniel J Rigden
Antimicrobial resistance within a wide range of infectious agents is a severe and growing public health threat. Antimicrobial peptides (AMPs) are among the leading alternatives to current antibiotics, exhibiting broad spectrum activity. Their activity is determined by numerous properties such as cationic charge, amphipathicity, size and amino acid composition. Currently, only around 10% of known AMP sequences have experimentally solved structures. To improve our understanding of the AMP structural universe we have carried out large scale ab initio 3D modelling of structurally uncharacterised AMPs that revealed similarities between predicted folds of the modelled sequences and structures of characterized AMPs...
February 1, 2018: Proteins
Guanhua Zhu, Wei Liu, Chenglong Bao, Dudu Tong, Hui Ji, Zuowei Shen, Daiwen Yang, Lanyuan Lu
The structural variations of multi-domain proteins with flexible parts mediate many biological processes, and a structure ensemble can be determined by selecting a weighted combination of representative structures from a simulated structure pool, producing the best fit to experimental constraints such as inter-atomic distance. In this study, a hybrid structure-based and physics-based atomistic force field with an efficient sampling strategy is adopted to simulate a model di-domain protein against experimental paramagnetic relaxation enhancement (PRE) data that correspond to distance constraints...
January 31, 2018: Proteins
Sherlyn Jemimah, M Michael Gromiha
Additivity in binding affinity of protein-protein complexes refers to the change in free energy of binding (ΔΔGbind ) for double (or multiple) mutations which is approximately equal to the sum of their corresponding single mutation ΔΔGbind values. In this work, we have explored the additivity effect of double mutants, which shows a linear relationship between the binding affinity of double and sum of single mutants with a correlation of 0.90. However, the comparison of ΔΔGbind values showed a mean absolute deviation of 0...
January 31, 2018: Proteins
Daniel R Grisham, Vikas Nanda
The zeta potential (ζ) is the effective charge energy of a solvated protein, describing the magnitude of electrostatic interactions in solution. It is commonly used in the assessment of adsorption processes and dispersion stability. Predicting ζ from molecular structure would be useful to the structure-based molecular design of drugs, proteins and other molecules that hold charge dependent function while remaining suspended in solution. One challenge in predicting ζ is identifying the location of the slip plane (XSP ), a distance from the protein surface where ζ is theoretically defined...
January 31, 2018: Proteins
Mehdi Mirzaie
Evaluation of protein structures needs a trustworthy potential function. Although several knowledge-based potential functions exist, the impact of different types of amino acids in the scoring functions has not been studied yet. Previously, we have reported the importance of nonlocal interactions in scoring function (based on Delaunay tessellation) in discrimination of native structures. Then, we have questioned the structural impact of hydrophobic amino acids in protein fold recognition. Therefore, a Hydrophobic Reduced Model (HRM) was designed to reduce protein structure of FS (Full Structure) into RS (Reduced Structure)...
January 31, 2018: Proteins
Jarjapu Mahita, Ramanathan Sowdhamini
Extensive research performed on Toll-like receptor (TLR) signalling has identified residues in the Toll/interleukin-1 receptor (TIR) domains that are essential for its proper functioning. Among these residues, those in BB loop are particularly significant as single amino acid mutations in this region can cause drastic changes in downstream signalling. However, while the effect of these mutations on the function is well studied (like the P681H mutation in TLR2, the A795P mutation in TLR3, and the P714H mutation in TLR4), their influence on the dynamics and inter-residue networks is not well understood...
January 31, 2018: Proteins
Jarjapu Mahita, Ramanathan Sowdhamini
The Toll-like receptors (TLRs) are critical components of the innate immune system due to their ability to detect conserved pathogen-associated molecular patterns, present in bacteria, viruses and other microorganisms. Ligand detection by TLRs leads to a signalling cascade, mediated by interactions among TIR domains present in the receptors, the bridging adaptors as well as sorting adaptors. The BB loop is a highly conserved region present in the TIR domain and is crucial for mediating interactions among TIR domain-containing proteins...
January 31, 2018: Proteins
Johnson Agniswamy, Renata A G Reis, Yuan-Fang Wang, Crystal Smitherman, Dan Su, Irene Weber, Giovanni Gadda
Nitronate monooxygenase (NMO) is an FMN-dependent enzyme that oxidizes the neurotoxin propionate 3-nitronate (P3N) and represents the best-known system for P3N detoxification in different organisms. The crystal structure of the first eukaryotic Class I NMO from Cyberlindnera saturnus (CsNMO) has been solved at 1.65 Å resolution and refined to an R-factor of 14.0%. The three-dimensional structures of yeast CsNMO and bacterial PaNMO are highly conserved with the exception of three additional loops on the surface in the CsNMO enzyme and differences in four active sites residues...
January 31, 2018: Proteins
Maxwell W Libbrecht, Jeffrey A Bilmes, William Stafford Noble
Selecting a non-redundant representative subset of sequences is a common step in many bioinformatics workflows, such as the creation of non-redundant training sets for sequence and structural models or selection of "operational taxonomic units" from metagenomics data. Previous methods for this task, such as CD-HIT, PISCES and UCLUST, apply a heuristic threshold-based algorithm that has no theoretical guarantees. We propose a new approach based on submodular optimization. Submodular optimization, a discrete analogue to continuous convex optimization, has been used with great success for other representative set selection problems...
January 18, 2018: Proteins
Hossein Batebi, Jovan Dragelj, Petra Imhof
Apurinic/apyrimidinic endonuclease 1 (Ape1) is an important metal-dependent enzyme in the base excision repair mechanism, responsible for the backbone cleavage of abasic DNA through a phosphate hydrolysis reaction. Molecular dynamics simulations of Ape1 complexed to its substrate DNA performed for models containing one or two Mg2+ -ions as cofactor located at different positions show a complex with one metal ion bound on the leaving group site of the scissile phosphate to be the most likely reaction-competent conformation...
January 18, 2018: Proteins
Keehyoung Joo, Seungryong Heo, InSuk Joung, Seung Hwan Hong, Sung Jong Lee, Jooyoung Lee
In CASP12, two types of data-assisted protein structure modeling were experimented. Either SAXS experimental data or cross-linking experimental data was provided for a selected number of CASP12 targets, so that the CASP12 predictor can utilize the given data for better protein structure modeling. We devised two separate energy terms for SAXS data and cross-linking data to drive model structures into more native-like structures that satisfy the given experimental data as much as possible. In CASP11, we successfully performed protein structure modeling using simulated sparse and ambiguously-assigned NOE data and/or correct residue-residue contact information, where the only energy term that folded the protein into its native structure was the term which was originated from the given experimental data...
January 17, 2018: Proteins
Rasim Murat Aydinkal, Elife Zerrin Bagci
Intrinsically disordered proteins/regions do not have well-defined secondary and tertiary structures, however, they are functional and it is critical to gain a deep understanding of their residue packing. The shape distributions methodology, which is usually utilized in pattern recognition, clustering and classification studies in computer science, may be adopted to study the residue packing of the proteins. In this study, shape distributions of the globular proteins and intrinsically disordered proteins (IDPs) were obtained to shed light on the residue packing of their structures...
January 17, 2018: Proteins
Huynh Minh Hung, Tran Dieu Hang, Minh Tho Nguyen
Hepatitis C virus (HCV), known as the leading cause of liver cirrhosis, viral hepatitis and hepatocellular carcinoma, has been affecting more than 150 million people globally. The HCV non-structure 3 (NS3) protease protein domain plays a key role in HCV replication and pathogenesis; and is currently a primary target for HCV antiviral therapy. Through unbiased molecular dynamics simulations which take advantage of the novel highly mobile membrane mimetic model, we constructed the membrane-bound state of the protein domain at the atomic level...
January 17, 2018: Proteins
Jamal Adiban, Yousef Jamali, Hashem Rafii-Tabar
CaV channels are transmembrane proteins that mediate and regulate ions fluxes across cell membranes, and they are activated in response to action potentials to allow Ca2+ influx. Since ion channels are composed of charge or polar groups, an external alternating electric field may affect the ion-selective membrane transport and the performance of the channel. In this paper, we have investigated the effect of an external GHz electric field on the dynamics of calcium ions in the selectivity filter of the CaV Ab channel...
January 11, 2018: Proteins
Tatjana Škrbić, Stefano Zamuner, Rolando Hong, Flavio Seno, Alessandro Laio, Antonio Trovato
Predicting the binding affinity between protein monomers is of paramount importance for the understanding of thermodynamical and structural factors that guide the formation of a complex. Several numerical techniques have been developed for the calculation of binding affinities with different levels of accuracy. Approaches such as thermodynamic integration and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) methodologies which account for well defined physical interactions offer good accuracy but are computationally demanding...
January 10, 2018: Proteins
Jinwoo Leem, Guy Georges, Jiye Shi, Charlotte M Deane
Side chain prediction is an integral component of computational antibody design and structure prediction. Current antibody modelling tools use backbone-dependent rotamer libraries with conformations taken from general proteins. Here we present our antibody-specific rotamer library, where rotamers are binned according to their IMGT position, rather than their local backbone geometry. We find that for some amino acid types at certain positions, only a restricted number of side chain conformations are ever observed...
January 10, 2018: Proteins
Melanie Vetter, Niels Boegholm, Anni Christensen, Sagar Bhogaraju, Marie B Andersen, Anna Lorentzen, Esben Lorentzen
Rab GTPases and their effectors, activators and guanine nucleotide exchange factors (GEFs) are essential for vesicular transport. Rab8 and its GEF Rabin8 function in formation of the cilium organelle important for developmental signaling and sensory reception. Here we show by size exclusion chromatography and analytical ultracentrifugation that Rabin8 exists in equilibrium between dimers and tetramers. The crystal structure of tetrameric Rabin8 GEF domain reveals an occluded Rab8 binding site suggesting that this oligomer is enzymatically inactive, a notion we verify experimentally using Rabin8/Rab8 GEF assays...
January 10, 2018: Proteins
Tadeusz L Ogorzalek, Greg L Hura, Adam Belsom, Kathryn H Burnett, Andriy Kryshtafovych, John A Tainer, Juri Rappsilber, Susan E Tsutakawa, Krzysztof Fidelis
Experimental data offers empowering constraints for structure prediction. These constraints can be used to filter equivalently scored models or more powerfully within optimization functions toward prediction. In CASP12, Small Angle X-ray Scattering (SAXS) and Cross-Linking Mass Spectrometry (CLMS) data, measured on an exemplary set of novel fold targets, were provided to the CASP community of protein structure predictors. As HT, solution-based techniques, SAXS and CLMS can efficiently measure states of the full-length sequence in its native solution conformation and assembly...
January 4, 2018: Proteins
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