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Michael Schantz Klausen, Martin Closter Jespersen, Henrik Nielsen, Kamilla Kjaergaard Jensen, Vanessa Isabell Jurtz, Casper Kaae Sønderby, Morten Otto Alexander Sommer, Ole Winther, Morten Nielsen, Bent Petersen, Paolo Marcatili
The ability to predict local structural features of a protein from the primary sequence is of paramount importance for unravelling its function in absence of experimental structural information. Two main factors affect the utility of potential prediction tools: their accuracy must enable extraction of reliable structural information on the proteins of interest, and their runtime must be low to keep pace with sequencing data being generated at a constantly increasing speed. Here, we present NetSurfP-2.0, a novel tool that can predict the most important local structural features with unprecedented accuracy and runtime...
February 20, 2019: Proteins
Jan Fehmi Sayılgan, Türkan Haliloğlu, Mehmet Gönen
Missense mutations have various effects on protein structures, also leading to distorted protein dynamics that plausibly affects the function. We hypothesized that missense mutations in cancer-related genes selectively target hinge-neighboring residues that orchestrate collective structural dynamics. To test our hypothesis, we selected 69 cancer-related genes from the Cancer Gene Census database and their representative protein structures from the Protein Data Bank. We first identified the hinge residues in two global modes of motion by applying the Gaussian Network Model...
February 20, 2019: Proteins
Hao Wu, Pedro Castenheira, Carlos Faro, Jordan Tang
Cardosin A is an aspartic protease present in large amount in the pistils of cardoon flowers. This protease is known to contain an -Arg-Gly-Asp- (RGD) motif located on the molecular surface. In this study we found that isolated recombinant cardosin A attached to human epithelial cells A549, mediated by the binding of its RGD motif to cell surface integrins. The cell bound cardosin A was internalized to endosomes and lysosomes and triggered the permeability of lysosomal membrane leading to apoptosis of the epithelial cells...
February 20, 2019: Proteins
Aharon Gomez, Esteban Vöhringer-Martinez
Thioredoxin is a protein that has been used as model system by various computational methods to predict the pKa of aspartate residue Asp26 which is 3.5 units higher than a solvent exposed one (e.g Asp20). Here, we use extensive atomistic molecular dynamics simulations of two different protonation states of Asp26 in combination with conformational analysis based on RMSD clustering and principle component analysis to identify representative conformations of the protein in solution. For each conformation the Gibbs free energy of proton transfer between Asp26 and Asp20, which is fully solvated in a loop region of the protein, is calculated with the Amber99sb force field in alchemical transformations...
February 4, 2019: Proteins
Raphael Petegrosso, Zhuliu Li, Molly A Srour, Yousef Saad, Wei Zhang, Rui Kuang
The global connectivities in very large protein similarity networks contain traces of evolution among the proteins for detecting protein remote evolutionary relations or structural similarities. To investigate how well a protein network captures the evolutionary information, a key limitation is the intensive computation of pairwise sequence similarities needed to construct very large protein networks. In this paper, we introduce Label Propagation on Low-rank Kernel Approximation (LP-LOKA) for searching massively large protein networks...
February 4, 2019: Proteins
A Kulandaisamy, S Binny Priya, R Sakthivel, Dmitrij Frishman, M Michael Gromiha
Mutations in transmembrane proteins (TMPs) have diverse effects on their structure and functions, which may lead to various diseases. In this present study, we have investigated variations in human membrane proteins and found that negatively charged to positively charged/polar and nonpolar to nonpolar changes are dominant in disease-causing and neutral mutations, respectively. Further, we analyzed the top ten preferred mutations in 14 different disease classes and found that each class has at least two Arg mutations...
February 3, 2019: Proteins
Jonathan Catazaro, Adam Caprez, David Swanson, Robert Powers
The functional evolution of proteins advances through gene duplication followed by functional drift, whereas molecular evolution occurs through random mutational events. Over time, protein active-site structures or functional epitopes remain highly conserved, which enables relationships to be inferred between distant orthologs or paralogs. In this study, we present the first functional clustering and evolutionary analysis of the RCSB Protein Data Bank (RCSB PDB) based on similarities between active-site structures...
February 3, 2019: Proteins
Ning Kang, Jiansheng Liu, Yaxue Zhao
Cell division control protein 42 homolog (Cdc42) influences a variety of cellular responses such as cell migration and polarity. Deregulation of Cdc42 has been associated with several human diseases and developmental disorders. Over-activation of Cdc42 through guanine nucleotide exchange factor (GEF) is a critical event for Cdc42 involved cancer metastasis. Members of DOCK family of GEF are important activators of Cdc42. However, this activation mechanism is still unknown. Molecular dynamics (MD) simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) calculations were employed to investigate the central step of the activation of Cdc42: the dissociation mechanism of GDP from Cdc42 via DOCK9...
February 3, 2019: Proteins
Maike Gräff, Patrick C F Buchholz, Peter Stockinger, Bettina Bommarius, Andreas S Bommarius, Jürgen Pleiss
The Short-chain Dehydrogenases/Reductases Engineering Database (SDRED) covers one of the largest known protein families (168,150 proteins). Assignment to the superfamilies of Classical and Extended SDRs was achieved by global sequence similarity and by identification of family-specific sequence motifs. Two standard numbering schemes were established for Classical and Extended SDRs that allow for the determination of conserved amino acid residues, such as cofactor specificity determining positions or superfamily specific sequence motifs...
February 3, 2019: Proteins
Yuki Hori, Hideki Fujiwara, Wataru Fujiwara, Koki Makabe
Many protein and peptide sequences are self-assembled into β-sheet-rich fibrous structures called amyloids. Their atomic details provide insights into fundamental knowledge related to amyloid diseases. To study the detailed structure of the amyloid, we have developed a model system that mimics the self-assembling process of the amyloid within a water-soluble protein, termed peptide self-assembly mimic (PSAM). PSAM enables capturing of a peptide sequence within a water-soluble protein, thus making structural and energetics-related studies possible...
January 26, 2019: Proteins
Emily F Gliniewicz, Kelly M Chambers, Elizabeth R De Leon, Diana Sibai, Helen C Campbell, Kathryn A McMenimen
Small heat shock proteins (sHsps) are molecular chaperones employed by various organisms to interact with a diverse range of substrates as the first line of defense against cellular protein aggregation. The N-terminal region (NTR) is implicated in defining features of sHsps; notably in their ability to form dynamic and polydisperse oligomers, as well as in their chaperone activity. The physiological relevance of oligomerization and the chemical-scale mode(s) of chaperone function remain undefined, likely due to sequence-level overlaps between functional regions of the proteins...
January 26, 2019: Proteins
Marko Tomin, Sanja Tomić
Aflatoxin oxidase (AFO), an enzyme isolated from Armillariella tabescens, has been reported to degrade aflatoxin B1 (AFB1). However, recent studies reported sequence and structure similarities with the dipeptidyl peptidase III (DPP III) family of enzymes and confirmed peptidase activity towards DPP III substrates. In light of these investigations, an extensive computational study was performed in order to improve understanding of the AFO functions. Steered MD simulations revealed long-range domain motions described as protein opening, characteristic for DPPs III and necessary for substrate binding...
January 25, 2019: Proteins
F Cazals, R Tetley
The root mean square deviation (RMSD) and the least RMSD are two widely used similarity measures in structural bioinformatics. Yet, they stem from global comparisons, possibly obliterating locally conserved motifs. We correct these limitations with the so-called combined, which mixes independent RMSD measures, each computed with its own rigid motion. The combined RMSD is relevant in two main scenarios, namely to compare (quaternary) structures based on motifs defined from the sequence (domains, SSE), and to compare structures based on structural motifs yielded by local structural alignment methods...
January 21, 2019: Proteins
Spraha Bhandari, Sreeparna Biswas, Anuradha Chaudhary, Somnath Dutta, Kaza Suguna
Small heat shock proteins (sHSPs) are ATP-independent molecular chaperones present ubiquitously in all kingdoms of life. The subunits are low molecular weight species that associate to form higher order structures. Under conditions of stress, sHSPs prevent aggregation of substrate proteins by undergoing rapid changes in their conformation or stoichiometry. Polydispersity and dynamic nature of these proteins have made structural investigations through crystallography a daunting task. In pathogens like Mycobacteria, sHSPs are immuno-dominant antigens, enabling survival of the pathogen within the host and contributing to disease persistence...
January 11, 2019: Proteins
George D Rose
The Ramachandran plot for backbone ϕ,ψ-angles in a blocked mono-peptide has played a central role in understanding protein structure. Curiously, a similar analysis for side chain χ-angles has been comparatively neglected. Instead, efforts have focused on compiling various types of side chain libraries extracted from proteins of known structure. Departing from this trend, the following analysis presents backbone-based maps of side chains in blocked mono-peptides. As in the original ϕ,ψ-plot, these maps are derived solely from hard-sphere steric repulsion...
January 10, 2019: Proteins
Shruti Khare, Munmun Bhasin, Anusmita Sahoo, Raghavan Varadarajan
Structure prediction methods often generate a large number of models for a target sequence. Even if the correct fold for the target sequence is sampled in this dataset, it is difficult to distinguish it from other decoy structures. An attempt to solve this problem using experimental mutational sensitivity data for the CcdB protein was described previously by exploiting the correlation of residue depth with mutational sensitivity (r ~ 0.6). We now show that such a correlation extends to four other proteins with localized active-sites, and for which saturation mutagenesis datasets exist...
January 7, 2019: Proteins
Chun Ye, Chengtao Ding, Rongsheng Ma, Junfeng Wang, Zhiyong Zhang
Adenylate kinase is a monomeric phosphotransferase with important biological function in regulating concentration of ATP in cells, by transferring the terminal phosphate group from ATP to AMP and forming two ADP molecules. During this reaction, the kinase may undergo a large conformational transition, forming different states with its substrates. Although many structures of the protein are available, atomic details of the whole process remain unclear. In this paper, we use both conventional molecular dynamics simulation and an enhanced sampling technique called parallel cascade selection molecular dynamics simulation to explore different conformational states of the Escherichia coli adenylate kinase...
January 7, 2019: Proteins
Christopher M Singer, Diana Joy, Donald J Jacobs, Irina V Nesmelova
DD[E/D]-transposases catalyze the multistep reaction of cut-and-paste DNA transposition. Structurally, several DD[E/D]-transposases have been characterized, revealing a multi-domain structure with the catalytic domain possessing the RNase H-like structural motif that brings three catalytic residues (D, D, and E or D) into close proximity for the catalysis. However, the dynamic behavior of DD[E/D]-transposases during transposition remains poorly understood. Here, we analyze the rigidity and flexibility characteristics of two representative DD[E/D]-transposases Mos1 and Sleeping Beauty (SB) using the minimal Distance Constraint Model (mDCM)...
December 24, 2018: Proteins
Antonio Marinho da Silva Neto, Samuel Reghim Silva, Michele Vendruscolo, Carlo Camilloni, Rinaldo Wander Montalvao
The lack of a proper mathematical language to represent protein conformational space remains a problem to be solved on protein flexibility analyses. A differential geometry (DG) representation of protein structures can provide a tool to overcome current limitations of popular representations. Here a DG-based representation of protein backbone is explored on the analyses of protein conformational ensembles. The protein backbone is represented as a 3D regular curve described by curvature, κ, and torsion, τ, values per residue...
December 23, 2018: Proteins
Wenbo Yu, Sunhwan Jo, Sirish Kaushik Lakkaraju, David J Weber, Alexander D MacKerell
Protein docking methods are powerful computational tools to study protein-protein interactions (PPI). While a significant number of docking algorithms have been developed, they are usually based on rigid protein models or with limited considerations of protein flexibility and the desolvation effect is rarely considered in docking energy functions, which may lower the accuracy of the predictions. To address these issues, we introduce a PPI energy function based on the Site-Identification by Ligand Competitive Saturation (SILCS) framework and utilize the fast Fourier transform (FFT) correlation approach...
December 23, 2018: Proteins
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