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Biological Assembly Comparison with VAST+ [chapter]

Thomas Madej, Aron Marchler-Bauer, Christopher Lanczycki, Dachuan Zhang, Stephen H. Bryant
2020 Msphere  
The VAST+ algorithm is an efficient, simple, and elegant solution to the problem of comparing the atomic structures of biological assemblies. Given two protein assemblies, it takes as input all the pairwise structural alignments of the component proteins. It then clusters the rotation matrices from the pairwise superpositions, with the clusters corresponding to subsets of the two assemblies that may be aligned and well superposed. It uses the Vector Alignment Search Tool (VAST) protein-protein
more » ... omparison method for the input structural alignments, but other methods could be used, as well. From a chosen cluster, an "original" alignment for the assembly may be defined by simply combining the relevant input alignments. However, it is often useful to reduce/trim the original alignment, using a Monte Carlo refinement algorithm, which allows biologically relevant conformational differences to be more readily detected and observed. The method is easily extended to include RNA or DNA molecules. VAST+ results may be accessed via the URL https://www.ncbi.nlm.nih.gov/Structure , then entering a PDB accession or terms in the search box, and using the link [VAST+] in the upper right corner of the Structure Summary page.
doi:10.1007/978-1-0716-0270-6_13 pmid:32006286 fatcat:mkbmpwjbsfhcbniljfzklm5x6e

Modeling Effects of Human Single Nucleotide Polymorphisms on Protein-Protein Interactions

Shaolei Teng, Thomas Madej, Anna Panchenko, Emil Alexov
2009 Biophysical Journal  
A large set of three-dimensional structures of 264 protein-protein complexes with known nonsynonymous single nucleotide polymorphisms (nsSNPs) at the interface was built using homology-based methods. The nsSNPs were mapped on the proteins' structures and their effect on the binding energy was investigated with CHARMM force field and continuum electrostatic calculations. Two sets of nsSNPs were studied: disease annotated Online Mendelian Inheritance in Man (OMIM) and nonannotated (non-OMIM). It
more » ... as demonstrated that OMIM nsSNPs tend to destabilize the electrostatic component of the binding energy, in contrast with the effect of non-OMIM nsSNPs. In addition, it was shown that the change of the binding energy upon amino acid substitutions is not related to the conservation of the net charge, hydrophobicity, or hydrogen bond network at the interface. The results indicate that, generally, the effect of nsSNPs on protein-protein interactions cannot be predicted from amino acids' physico-chemical properties alone, since in many cases a substitution of a particular residue with another amino acid having completely different polarity or hydrophobicity had little effect on the binding energy. Analysis of sequence conservation showed that nsSNP at highly conserved positions resulted in a large variance of the binding energy changes. In contrast, amino acid substitutions corresponding to nsSNPs at nonconserved positions, on average, were not found to have a large effect on binding affinity. pKa calculations were performed and showed that amino acid substitutions could change the wild-type proton uptake/release and thus resulting in different pH-dependence of the binding energy.
doi:10.1016/j.bpj.2008.12.3904 pmid:19289044 pmcid:PMC2717281 fatcat:m5vvopxlvrdo7mo6jl4nlaxfrq

Evolutionary, Physicochemical, and Functional Mechanisms of Protein Homooligomerization [chapter]

Hafumi Nishi, Kosuke Hashimoto, Thomas Madej, Anna R. Panchenko
2013 Progress in Molecular Biology and Translational Science  
Protein homooligomers afford several important benefits for the cell; they mediate and regulate gene expression, activity of many enzymes, ion channels, receptors, and cell-cell adhesion processes. The evolutionary and physical mechanisms of oligomer formation are very diverse and are not well understood. Certain homooligomeric states may be conserved within protein subfamilies and between different subfamilies, therefore providing the specificity to particular substrates while minimizing
more » ... ctions with unwanted partners. In addition, transitions between different oligomeric states may regulate protein activity and support the switch between different pathways. In this chapter, we summarize the biological importance of homooligomeric assemblies, physicochemical properties of their interfaces, experimental methods for their identification, their evolution, and role in human diseases.
doi:10.1016/b978-0-12-386931-9.00001-5 pmid:23663963 pmcid:PMC3786560 fatcat:htbgrqpizvd5hpy6xrwvrdvndy

Accurate Treatment of Comptonization in X-ray Illuminated Accretion Disks [article]

Javier A. García, Ekaterina Sokolova-Lapa, Thomas Dauser, Jerzy Madej, Agata Różańska, Agnieszka Majczyna, Fiona A. Harrison, Jörn Wilms
2020 arXiv   pre-print
We note that there is a misprint in the definition of γ * in Madej et al. (2017) , Eq. 4. See Erratum by Madej et al. (2019) . driveSRF codebase:https://github.com/jajgarcia/ exact Compton  ...  The redistribution function accurate for photon energies approaching electron rest mass, was given by Guilbert (1981) and used by Madej & Rózańska (2000) and Madej & Różańska (2004) in case of irradiated  ... 
arXiv:2005.04852v1 fatcat:yjwfc7ofyzgzdkfvswbst5a7iq

Structural similarity of loops in protein families: toward the understanding of protein evolution

Anna R Panchenko, Thomas Madej
2005 BMC Evolutionary Biology  
Protein evolution and protein classification are usually inferred by comparing protein cores in their conserved aligned parts. Structurally aligned protein regions are separated by less conserved loop regions, where sequence and structure locally deviate from each other and do not superimpose well. Our results indicate that even longer protein loops can not be viewed as "random coils" and for the majority of protein families in our test set there exists a linear correlation between the measures
more » ... of sequence similarity and loop structural similarity. Results suggest that distance matrices derived from the loop (dis)similarity measure may produce in some cases more reliable cluster trees compared to the distance matrices based on the conventional measures of sequence and structural (dis)similarity. We show that by considering "dissimilar" loop regions rather than only conserved core regions it is possible to improve our understanding of protein evolution.
doi:10.1186/1471-2148-5-10 pmid:15691378 pmcid:PMC549550 fatcat:rb36whfyxfb2tfmilav3mkdcke

Long-term trends in evolution of indels in protein sequences

Yuri Wolf, Thomas Madej, Vladimir Babenko, Benjamin Shoemaker, Anna R Panchenko
2007 BMC Evolutionary Biology  
In this paper we describe an analysis of the size evolution of both protein domains and their indels, as inferred by changing sizes of whole domains or individual unaligned regions or "spacers". We studied relatively early evolutionary events and focused on protein domains which are conserved among various taxonomy groups. We found that more than one third of all domains have a statistically significant tendency to increase/decrease in size in evolution as judged from the overall domain size
more » ... tribution as well as from the size distribution of individual spacers. Moreover, the fraction of domains and individual spacers increasing in size is almost twofold larger than the fraction decreasing in size. We showed that the tolerance to insertion and deletion events depends on the domain's taxonomy span. Eukaryotic domains are depleted in insertions compared to the overall test set, namely, the number of spacers increasing in size is about the same as the number of spacers decreasing in size. On the other hand, ancient domain families show some bias towards insertions or spacers which grow in size in evolution. Domains from several Gene Ontology categories also demonstrate certain tendencies for insertion or deletion events as inferred from the analysis of spacer sizes.
doi:10.1186/1471-2148-7-19 pmid:17298668 pmcid:PMC1805498 fatcat:6klaximiwrefzcrrjvckrerfra

Knowledge-based annotation of small molecule binding sites in proteins

Ratna R Thangudu, Manoj Tyagi, Benjamin A Shoemaker, Stephen H Bryant, Anna R Panchenko, Thomas Madej
2010 BMC Bioinformatics  
The combined score is designed to rank the most biologically relevant sites at the top. { } (5) Additional material * Correspondence: panch@ncbi.nlm.nih.gov, madej@ncbi.nlm.nih.gov National Center for  ... 
doi:10.1186/1471-2105-11-365 pmid:20594344 pmcid:PMC2909224 fatcat:em4aumldr5acvds6d2f3qpzone

Threading analysis suggests that the obese gene product may be a helical cytokine

Thomas Madej, Mark S. Boguski, Stephen H. Bryant
1995 FEBS Letters  
The ob gene encodes a protein that, in mutant form, is associated with obesity and type II diabetes in mice. Sequence analysis has revealed no similarities to other proteins, however, and no clues as to possible functions. The possibility nonetheless remains that ob is functionally or ancestrally related to other proteins, whose sequences are divergent to the point that only a comparison of three-dimensional structures might detect relationship. To explore this possibility, we conduct a
more » ... ng' search of a 3-dimensional structure database, to determine whether the ob protein might adopt a fold similar to any known structure. This search reveals that the ob sequence is compatible, at a significance level of P < 0.05, with structures from the family of helical cytokines that includes interleukin-2 and growth hormone. A structural model of ob based upon these results is physically and biologically plausible and leads to testable predictions, including the prediction that ob may activate the JAK-STAT pathway, via binding to a receptor resembling those of the cytokine family.
doi:10.1016/0014-5793(95)00977-h pmid:7589424 fatcat:2thxena5ijbavhd7h2io2qr4pu

Functional States of Homooligomers: Insights from the Evolution of Glycosyltransferases

Kosuke Hashimoto, Thomas Madej, Stephen H. Bryant, Anna R. Panchenko
2010 Journal of Molecular Biology  
Glycosylation is an important aspect of epigenetic regulation. Glycosyltransferase is a key enzyme in the biosynthesis of glycans, which glycosylates more than half of all proteins in eukaryotes and is involved in a wide range of biological processes. It has been suggested previously that homooligomerization in glycosyltransferases and other proteins might be crucial for their function. In this study, we explore functional homooligomeric states of glycosyltransferases in various organisms,
more » ... their evolution and perform comparative analyses to find structural features which can mediate or disrupt the formation of different homooligomers. First we make a structure-based classification of the diverse superfamily of glycosyltransferases and confirm that the majority of the structures are indeed clustered into the GT-A or GT-B folds. We find that homooligomeric glycosyltransferases appear to be as ancient as monomeric glycosyltransferases and go back in evolution to the last universal common ancestor (LUCA). Moreover, we show that interface residues have significant bias to be gapped out or unaligned in the monomers implying that they might represent features crucial for oligomer formation. Structural analysis of these features reveals that the vast majority of them represent loops, terminal regions and helices indicating that these secondary structure elements mediate the formation of glycosyltransferases' homooligomers and directly contribute to the specific binding. We also observe relatively short protein regions which disrupt the homodimer interactions although such cases are rare. These results suggest that relatively small structural changes in the non-conserved regions may contribute to the formation of different functional oligomeric states and might be important in regulation of enzyme activity through homooligomerization.
doi:10.1016/j.jmb.2010.03.059 pmid:20381499 pmcid:PMC2896236 fatcat:5tlom6zxwncf7ha5xqlmb5h7ki

Protein homologous cores and loops: important clues to evolutionary relationships between structurally similar proteins

Thomas Madej, Anna R Panchenko, Jie Chen, Stephen H Bryant
2007 BMC Structural Biology  
More recently, Panchenko and Madej have introduced the "Loop Hausdorff Measure" (LHM), which measures the (average) amount of deviation between the loop regions in a pair of superposed protein structures  ... 
doi:10.1186/1472-6807-7-23 pmid:17425794 pmcid:PMC1852803 fatcat:inr2xhveineidpyujgpmolqnpe

Channel responses to varying sediment input: A flume experiment modeled after Redwood Creek, California

Mary Ann Madej, Diane G. Sutherland, Thomas E. Lisle, Bonnie Pryor
2009 Geomorphology  
Thomas Dunklin videographed the flume runs.  ...  (Photo by Thomas Dunklin.)Fig. 14. Relation between sediment storage and transport capacity of flume channel during aggradational and degradational cycles.  ... 
doi:10.1016/j.geomorph.2008.07.017 fatcat:gksi6unci5hclmb3ekj2llaxja

Homology Inference of Protein-Protein Interactions via Conserved Binding Sites

Manoj Tyagi, Ratna R. Thangudu, Dachuan Zhang, Stephen H. Bryant, Thomas Madej, Anna R. Panchenko, Vladimir N. Uversky
2012 PLoS ONE  
The coverage and reliability of protein-protein interactions determined by high-throughput experiments still needs to be improved, especially for higher organisms, therefore the question persists, how interactions can be verified and predicted by computational approaches using available data on protein structural complexes. Recently we developed an approach called IBIS (Inferred Biomolecular Interaction Server) to predict and annotate protein-protein binding sites and interaction partners,
more » ... is based on the assumption that the structural location and sequence patterns of protein-protein binding sites are conserved between close homologs. In this study first we confirmed high accuracy of our method and found that its accuracy depends critically on the usage of all available data on structures of homologous complexes, compared to the approaches where only a non-redundant set of complexes is employed. Second we showed that there exists a trade-off between specificity and sensitivity if we employ in the prediction only evolutionarily conserved binding site clusters or clusters supported by only one observation (singletons). Finally we addressed the question of identifying the biologically relevant interactions using the homology inference approach and demonstrated that a large majority of crystal packing interactions can be correctly identified and filtered by our algorithm. At the same time, about half of biological interfaces that are not present in the protein crystallographic asymmetric unit can be reconstructed by IBIS from homologous complexes without the prior knowledge of crystal parameters of the query protein.
doi:10.1371/journal.pone.0028896 pmid:22303436 pmcid:PMC3269416 fatcat:662tgug3ujgwdktzkc5axdusl4

Modulating Protein–Protein Interactions with Small Molecules: The Importance of Binding Hotspots

Ratna Rajesh Thangudu, Stephen H. Bryant, Anna R. Panchenko, Thomas Madej
2012 Journal of Molecular Biology  
Edited by B. Honig Keywords: protein structures; molecular interactions; protein-protein interactions; drug development hotspots The modulation of protein-protein interactions (PPIs) by small drug-like molecules is a relatively new area of research and has opened up new opportunities in drug discovery. However, the progress made in this area is limited to a handful of known cases of small molecules that target specific diseases. With the increasing availability of protein structure complexes,
more » ... is highly important to devise strategies exploiting homologous structure space on a large scale for discovering putative PPIs that could be attractive drug targets. Here, we propose a scheme that allows performing large-scale screening of all protein complexes and finding putative small-molecule and/or peptide binding sites overlapping with protein-protein binding sites (so-called "multibinding sites"). We find more than 600 nonredundant proteins from 60 protein families with multibinding sites. Moreover, we show that the multibinding sites are mostly observed in transient complexes, largely overlap with the binding hotspots and are more evolutionarily conserved than other interface sites. We investigate possible mechanisms of how small molecules may modulate protein-protein binding and discuss examples of new candidates for drug design.
doi:10.1016/j.jmb.2011.12.026 pmid:22198293 pmcid:PMC3433052 fatcat:fofx6a7zgreprbztv3epdl6dvy

Evolutionary plasticity of protein families: Coupling between sequence and structure variation

Anna R. Panchenko, Yuri I. Wolf, Larisa A. Panchenko, Thomas Madej
2005 Proteins: Structure, Function, and Bioinformatics  
In this work we examine how protein structural changes are coupled with sequence variation in the course of evolution of a family of homologs. The sequence-structure correlation analysis performed on 81 homologous protein families shows that the majority of them exhibit statistically significant linear correlation between the measures of sequence and structural similarity. We observed, however, that there are cases where structural variability cannot be mainly explained by sequence variation,
more » ... ch as protein families with a number of disulfide bonds. To understand whether structures from different families and/or folds evolve in the same manner, we compared the degrees of structural change per unit of sequence change ("the evolutionary plasticity of structure") between those families with a significant linear correlation. Using rigorous statistical procedures we find that, with a few exceptions, evolutionary plasticity does not show a statistically significant difference between protein families. Similar sequence-structure analysis performed for protein loop regions shows that evolutionary plasticity of loop regions is greater than for the protein core.
doi:10.1002/prot.20644 pmid:16184609 pmcid:PMC1941674 fatcat:vah3vmcbb5hurmomjatiocw3r4

MMDB and VAST+: tracking structural similarities between macromolecular complexes

Thomas Madej, Christopher J. Lanczycki, Dachuan Zhang, Paul A. Thiessen, Renata C. Geer, Aron Marchler-Bauer, Stephen H. Bryant
2013 Nucleic Acids Research  
The computational detection of similarities between protein 3D structures has become an indispensable tool for the detection of homologous relationships, the classification of protein families and functional inference. Consequently, numerous algorithms have been developed that facilitate structure comparison, including rapid searches against a steadily growing collection of protein structures. To this end, NCBI's Molecular Modeling Database (MMDB), which is based on the Protein Data Bank (PDB),
more » ... maintains a comprehensive and up-to-date archive of protein structure similarities computed with the Vector Alignment Search Tool (VAST). These similarities have been recorded on the level of single proteins and protein domains, comprising in excess of 1.5 billion pairwise alignments. Here we present VAST+, an extension to the existing VAST service, which summarizes and presents structural similarity on the level of biological assemblies or macromolecular complexes. VAST+simplifies structure neighboring results and shows, for macromolecular complexes tracked in MMDB, lists of similar complexes ranked by the extent of similarity. VAST+ replaces the previous VAST service as the default presentation of structure neighboring data in NCBI's Entrez query and retrieval system. MMDB and VAST+ can be accessed via http:// www.ncbi.nlm.nih.gov/Structure.
doi:10.1093/nar/gkt1208 pmid:24319143 pmcid:PMC3965051 fatcat:ahptxplnojbqtglstonppvu33i
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