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Rigidity analysis of protein biological assemblies and periodic crystal structures

BMC BIOINFORMATICS 2013年第Sup18期14卷 S2-S2页

作者： Jagodzinski, Filip Clark, Pamela Grant, Jessica Liu, Tiffany Monastra, Samantha Streinu, Ileana Smith Coll Dept Math Northampton MA 01063 USA Smith Coll Dept Biol Sci Northampton MA 01063 USA Cent Washington Univ Dept Comp Sci Ellensburg WA 98926 USA Smith Coll Dept Comp Sci Northampton MA 01063 USA

Background: We initiate in silico rigidity-theoretical studies of biological assemblies and small crystals for protein structures. The goal is to determine if, and how, the interactions among neighboring cells and subchains affect the flexibility of a molecule in its crystallized state. We use experimental X-ray crystallography data from the protein data bank (PDB). The analysis relies on an effcient graph-based algorithm. Computational experiments were performed using new protein rigidity analysis tools available in the new release of our KINARI-Web server http://***. Results: We provide two types of results: on biological assemblies and on crystals. We found that when only isolated subchains are considered, structural and functional information may be missed. Indeed, the rigidity of biological assemblies is sometimes dependent on the count and placement of hydrogen bonds and other interactions among the individual subchains of the biological unit. Similarly, the rigidity of small crystals may be affected by the interactions between atoms belonging to different unit cells. We have analyzed a dataset of approximately 300 proteins, from which we generated 982 crystals (some of which are biological assemblies). We identified two types of behaviors. (a) Some crystals and/or biological assemblies will aggregate into rigid bodies that span multiple unit cells/asymmetric units. Some of them create substantially larger rigid cluster in the crystal/biological assembly form, while in other cases, the aggregation has a smaller effect just at the interface between the units. (b) In other cases, the rigidity properties of the asymmetric units are retained, because the rigid bodies did not combine. We also identified two interesting cases where rigidity analysis may be correlated with the functional behavior of the protein. This type of information, identified here for the first time, depends critically on the ability to create crystals and biological assemblies,

关键词： protein data bank Asymmetric Unit Symmetry Operation Rift Valley Fever Virus protein data bank code

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Multifunctionality and diversity of GDSL esterase/lipase gene family in rice (Oryza sativa L. japonica) genome: new insights from bioinformatics analysis

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BMC GENOMICS 2012年第1期13卷 309-309页

作者： Chepyshko, Hanna Lai, Chia-Ping Huang, Ming Liu, Jyung-Hurng Shaw, Jei-Fu Far E Univ Dept Food & Beverage Management Tainan 74448 Taiwan Natl Chung Hsing Univ Dept Food Sci & Biotechnol Taichung 402 Taiwan Natl Cheng Kung Univ Inst Biotechnol Tainan 701 Taiwan Natl Chung Hsing Univ Inst Genom & Bioinformat Taichung 40227 Taiwan I Shou Univ Dept Biol Sci & Technol Kaohsiung 84001 Taiwan Acad Sinica Agr Biotechnol Res Ctr Nankang 115 Taiwan

Background: GDSL esterases/lipases are a newly discovered subclass of lipolytic enzymes that are very important and attractive research subjects because of their multifunctional properties, such as broad substrate specificity and regiospecificity. Compared with the current knowledge regarding these enzymes in bacteria, our understanding of the plant GDSL enzymes is very limited, although the GDSL gene family in plant species include numerous members in many fully sequenced plant genomes. Only two genes from a large rice GDSL esterase/lipase gene family were previously characterised, and the majority of the members remain unknown. In the present study, we describe the rice OsGELP (Oryza sativa GDSL esterase/lipase protein) gene family at the genomic and proteomic levels, and use this knowledge to provide insights into the multifunctionality of the rice OsGELP enzymes. Results: In this study, an extensive bioinformatics analysis identified 114 genes in the rice OsGELP gene family. A complete overview of this family in rice is presented, including the chromosome locations, gene structures, phylogeny, and protein motifs. Among the OsGELPs and the plant GDSL esterase/lipase proteins of known functions, 41 motifs were found that represent the core secondary structure elements or appear specifically in different phylogenetic subclades. The specification and distribution of identified putative conserved clade-common and -specific peptide motifs, and their location on the predicted protein three dimensional structure may possibly signify their functional roles. Potentially important regions for substrate specificity are highlighted, in accordance with protein three-dimensional model and location of the phylogenetic specific conserved motifs. The differential expression of some representative genes were confirmed by quantitative real-time PCR. The phylogenetic analysis, together with protein motif architectures, and the expression profiling were analysed to predict the possib

关键词： Rice Chromosome protein data bank code Rice Organ Rice Genome Annotation Project Figure 4Additional File

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Characterisation of a cell wall-anchored protein of Staphylococcus saprophyticus associated with linoleic acid resistance

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BMC MICROBIOLOGY 2012年第1期12卷 8-8页

作者： King, Nathan P. Sakinc, Tuerkan Ben Zakour, Nouri L. Totsika, Makrina Heras, Begona Simerska, Pavla Shepherd, Mark Gatermann, Soeren G. Beatson, Scott A. Schembri, Mark A. Univ Queensland Sch Chem & Mol Biosci Australian Infect Dis Res Ctr Brisbane Qld 4072 Australia Ruhr Univ Bochum Inst Hyg & Microbiol Dept Med Microbiol D-44780 Bochum Germany Univ Queensland Inst Mol Biosci Brisbane Qld 4072 Australia Univ Med Ctr Freiburg Ctr Infect Dis & Travel Med Freiburg Germany Univ Kent Sch Biosci Canterbury CT2 7NJ Kent England

Background: The Gram-positive bacterium Staphylococcus saprophyticus is the second most frequent causative agent of community-acquired urinary tract infections (UTI), accounting for up to 20% of cases. A common feature of staphylococci is colonisation of the human skin. This involves survival against innate immune defenses including antibacterial unsaturated free fatty acids such as linoleic acid which act by disrupting bacterial cell membranes. Indeed, S. saprophyticus UTI is usually preceded by perineal skin colonisation. Results: In this study we identified a previously undescribed 73.5 kDa cell wall-anchored protein of S. saprophyticus, encoded on plasmid pSSAP2 of strain MS1146, which we termed S. saprophyticus surface protein F (SssF). The sssF gene is highly prevalent in S. saprophyticus clinical isolates and we demonstrate that the SssF protein is expressed at the cell surface. However, unlike all other characterised cell wall-anchored proteins of S. saprophyticus, we were unable to demonstrate a role for SssF in adhesion. SssF shares moderate sequence identity to a surface protein of Staphylococcus aureus (SasF) recently shown to be an important mediator of linoleic acid resistance. Using a heterologous complementation approach in a S. aureus sasF null genetic background, we demonstrate that SssF is associated with resistance to linoleic acid. We also show that S. saprophyticus strains lacking sssF are more sensitive to linoleic acid than those that possess it. Every staphylococcal genome sequenced to date encodes SssF and SasF homologues. proteins in this family share similar predicted secondary structures consisting almost exclusively of a-helices in a probable coiled-coil formation. Conclusions: Our data indicate that SssF is a newly described and highly prevalent surface-localised protein of S. saprophyticus that contributes to resistance against the antibacterial effects of linoleic acid. SssF is a member of a protein family widely disseminated through

关键词： Linoleic Acid Urinary Tract Infection Cell Surface Hydrophobicity protein data bank code Strain MS1146

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Creating PWMs of transcription factors using 3D structure-based computation of protein-DNA free binding energies

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BMC BIOINFORMATICS 2010年第1期11卷 1-15页

作者： Alamanova, Denitsa Stegmaier, Philip Kel, Alexander BIOBASE GmbH D-38304 Wolfenbuettel Germany

Background: Knowledge of transcription factor-DNA binding patterns is crucial for understanding gene transcription. Numerous DNA-binding proteins are annotated as transcription factors in the literature, however, for many of them the corresponding DNA-binding motifs remain uncharacterized. Results: The position weight matrices (PWMs) of transcription factors from different structural classes have been determined using a knowledge-based statistical potential. The scoring function calibrated against crystallographic data on protein-DNA contacts recovered PWMs of various members of widely studied transcription factor families such as p53 and NF-kappa B. Where it was possible, extensive comparison to experimental binding affinity data and other physical models was made. Although the p50p50, p50RelB, and p50p65 dimers belong to the same family, particular differences in their PWMs were detected, thereby suggesting possibly different in vivo binding modes. The PWMs of p63 and p73 were computed on the basis of homology modeling and their performance was studied using upstream sequences of 85 p53/p73-regulated human genes. Interestingly, about half of the p63 and p73 hits reported by the Match algorithm in the altogether 126 promoters lay more than 2 kb upstream of the corresponding transcription start sites, which deviates from the common assumption that most regulatory sites are located more proximal to the TSS. The fact that in most of the cases the binding sites of p63 and p73 did not overlap with the p53 sites suggests that p63 and p73 could influence the p53 transcriptional activity cooperatively. The newly computed p50p50 PWM recovered 5 more experimental binding sites than the corresponding TRANSFAC matrix, while both PWMs showed comparable receiver operator characteristics. Conclusions: A novel algorithm was developed to calculate position weight matrices from protein-DNA complex structures. The proposed algorithm was extensively validated against experimental data

关键词： protein data bank Root Mean Square Deviation Sequence Logo protein data bank code Position Weight Matrice

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The protein-DNA Interface database

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BMC BIOINFORMATICS 2010年第1期11卷 262-262页

作者： Norambuena, Tomas Melo, Francisco Pontificia Univ Catolica Chile Fac Ciencias Biol Dept Mol Genet & Microbiol Santiago Chile

The protein-DNA Interface database (PDIdb) is a repository containing relevant structural information of protein-DNA complexes solved by X-ray crystallography and available at the protein data bank. The database includes a simple functional classification of the protein-DNA complexes that consists of three hierarchical levels: Class, Type and Subtype. This classification has been defined and manually curated by humans based on the information gathered from several sources that include PDB, PubMed, CATH, SCOP and COPS. The current version of the database contains only structures with resolution of 2.5 angstrom or higher, accounting for a total of 922 entries. The major aim of this database is to contribute to the understanding of the main rules that underlie the molecular recognition process between DNA and proteins. To this end, the database is focused on each specific atomic interface rather than on the separated binding partners. Therefore, each entry in this database consists of a single and independent protein-DNA interface. We hope that PDIdb will be useful to many researchers working in fields such as the prediction of transcription factor binding sites in DNA, the study of specificity determinants that mediate enzyme recognition events, engineering and design of new DNA binding proteins with distinct binding specificity and affinity, among others. Finally, due to its friendly and easy-to-use web interface, we hope that PDIdb will also serve educational and teaching purposes.

关键词： protein data bank protein data bank code Interaction Class Biological Unit protein data bank File

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3D-interologs: an evolution database of physical protein- protein interactions across multiple genomes

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BMC GENOMICS 2010年第Sup3期11卷 S7-S7页

作者： Lo, Yu-Shu Chen, Yung-Chiang Yang, Jinn-Moon Natl Chiao Tung Univ Dept Biol Sci & Technol Hsinchu Taiwan Natl Chiao Tung Univ Inst Bioinformat Hsinchu Taiwan Natl Chiao Tung Univ Core Facil Struct Bioinformat Hsinchu Taiwan

Background: Comprehensive exploration of protein-protein interactions is a challenging route to understand biological processes. For efficiently enlarging protein interactions annotated with residue-based binding models, we proposed a new concept "3D-domain interolog mapping" with a scoring system to explore all possible protein pairs between the two homolog families, derived from a known 3D-structure dimmer (template), across multiple species. Each family consists of homologous proteins which have interacting domains of the template for studying domain interface evolution of two interacting homolog families. Results: The 3D-interologs database records the evolution of protein-protein interactions database across multiple species. Based on "3D-domain interolog mapping" and a new scoring function, we infer 173,294 protein-protein interactions by using 1,895 three-dimensional (3D) structure heterodimers to search the UniProt database (4,826,134 protein sequences). The 3D-interologs database comprises 15,124 species and 283,980 protein-protein interactions, including 173,294 interactions (61%) and 110,686 interactions (39%) summarized from the IntAct database. For a protein-protein interaction, the 3D-interologs database shows functional annotations (e. g. Gene Ontology), interacting domains and binding models (e. g. hydrogen-bond interactions and conserved residues). Additionally, this database provides couple-conserved residues and the interacting evolution by exploring the interologs across multiple species. Experimental results reveal that the proposed scoring function obtains good agreement for the binding affinity of 275 mutated residues from the ASEdb. The precision and recall of our method are 0.52 and 0.34, respectively, by using 563 non-redundant heterodimers to search on the Integr8 database (549 complete genomes). Conclusions: Experimental results demonstrate that the proposed method can infer reliable physical protein-protein interactions and be useful for

关键词： protein data bank Multiple Species Query protein Contact Residue protein data bank code

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Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100

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BMC BIOINFORMATICS 2009年第s15期10卷 1-11页

作者： Dastidar, Shubhra Ghosh Lane, David P. Verma, Chandra S. ASTAR Bioinformat Inst Singapore 138671 Singapore Inst Mol & Cell Biol ASTAR Singapore 138673 Singapore Natl Univ Singapore Dept Biol Sci Singapore 119077 Singapore Nanyang Technol Univ Sch Biol Sci Singapore 639798 Singapore

Background: The tumor suppressor protein p53 is regulated by the ubiquitin ligase MDM2 which down-regulates p53. In tumours with overexpressed MDM2, the p53-MDM2 interaction can be interrupted by a peptide or small molecule to stabilize p53 as a therapeutic strategy. Structural and biochemical/mutagenesis data show that p53 has 3 hydrophobic residues F19, W23 and L26 that embed into the ligand binding pocket of MDM2 which is highly plastic in nature and can modulate its size to accommodate a variety of ligands. This binding pocket is primarily dependent on the orientation of a particular residue, Y100. We have studied the role of the dynamics of Y100 in p53 recognition. Results: Molecular dynamics simulations show that the Y100 side chain can be in "open" or "closed" states with only the former enabling complex formation. When both p53 and MDM2 are in near native conformations, complex formation is rapid and is driven by the formation of a hydrogen bond between W23 of p53 and L54 of MDM2 or by the embedding of F19 of p53 into MDM2. The transition of Y100 from "closed" to "open" can increase the size of the binding site. Interconversions between these two states can be induced by the N-terminal region of MDM2 or by the conformations of the p53 peptides. Conclusion: Molecular dynamics simulations have revealed how the binding of p53 to MDM2 is modulated by the conformational mobility of Y100 which is the gatekeeper residue in MDM2. The mobility of this residue can be modulated by the conformations of p53 and the Nterminal lid region of MDM2.

关键词： Binding Pocket Helical Conformation protein data bank code Root Mean Square Deviation Side Chain Hydroxyl

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Immunological hotspots analyzed by docking simulations: evidence for a general mechanism in pemphigus vulgaris pathology and transformation

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BMC IMMUNOLOGY 2008年第1期9卷 30-30页

作者： Tong, Joo Chuan Sinha, Animesh A. Inst Infocomm Res Data Mining Dept Singapore 119613 Singapore Michigan State Univ Coll Human Med Div Dermatol & Cutaneous Sci E Lansing MI 48824 USA

Background: Pemphigus vulgaris (PV) is an acquired autoimmune blistering disorder in which greater than 80% of active patients produce autoantibodies to the desmosomal protein desmogelin 3 (Dsg3). As the disease progresses, 40-50% of patients may also develop reactivity to a second component of the desmosomal complex, desmogelin 1 (Dsg1). T cells are clearly required for the production of autoantibodies in PV. However, few T-cell specificities within Dsg3 or Dsg1 have been reported to date, and the precise role of T-cells in disease pathogenesis and evolution remains poorly understood. In particular, no studies have addressed the immunological mechanisms that underlie the observed clinical heterogeneity in pemphigus. We report here a structure-based technique for the screening of DRB1*0402-specific immunological (T-cell epitope) hotspots in both Dsg3 and Dsg1 glycoproteins. Results: High predictivity was obtained for DRB1*0402 (r(2) = 0.90, s = 1.20 kJ/mol, q(2) = 0.82, s(press) = 1.61 kJ/mol) predictive model, compared to experimental data. In silico mapping of the T-cell epitope repertoires in Dsg3 and Dsg1 glycoproteins revealed that the potential immunological hotspots of both target autoantigens are highly conserved, despite limited sequence identity (54% identical, 72% similar). A similar number of well-conserved (18%) high-affinity binders were predicted to exist within both Dsg3 and Dsg1, with analogous distribution of binding registers. Conclusion: This study provides interesting new insights into the possible mechanism for PV disease progression. Our data suggests that the potential T-cell epitope repertoires encoded in Dsg1 and Dsg3 is substantially overlapping, and it may be possible to apply a common, antigen-specific therapeutic strategy with efficacy across distinct clinical phases of disease.

关键词： Pemphigus Epitope Spreading protein data bank code Autoreactive Lymphocyte Antigen Mimicry

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Kappa-alpha plot derived structural alphabet and BLOSUM-like substitution matrix for rapid search of protein structure database

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GENOME BIOLOGY 2007年第3期8卷 R31-R31页

作者： Tung, Chi-Hua Huang, Jhang-Wei Yang, Jinn-Moon Natl Chiao Tung Univ Inst Bioinformat Hsinchu 30050 Taiwan Natl Chiao Tung Univ Dept Biol Sci & Technol Hsinchu 30050 Taiwan Natl Chiao Tung Univ Core Facil Struct Bioinformat Hsinchu 30050 Taiwan

We present a novel protein structure database search tool, 3D- BLAST, that is useful for analyzing novel structures and can return a ranked list of alignments. This tool has the features of BLAST ( for example, robust statistical basis, and effective and reliable search capabilities) and employs a kappa-alpha (kappa, alpha) plot derived structural alphabet and a new substitution matrix. 3D- BLAST searches more than 12,000 protein structures in 1.2 s and yields good results in zones with low sequence similarity.

关键词： protein data bank Additional data File Query protein Substitution Matrix protein data bank code

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Prediction of desmoglein-3 peptides reveals multiple shared T-cell epitopes in HLA DR4- and DR6-associated Pemphigus vulgaris

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BMC BIOINFORMATICS 2006年第5-Sup期7卷 S7-S7页

作者： Tong, Joo Chuan Tan, Tin Wee Sinha, Animesh A. Ranganathan, Shoba Michigan State Univ Coll Human Med Div Dermatol & Cutaneous Sci Ctr Investigat Dermatol E Lansing MI 48824 USA Inst Infocomm Res Singapore 119613 Singapore Natl Univ Singapore Yong Loo Lin Sch Med Dept Biochem Singapore 117597 Singapore Macquarie Univ Dept Chem & Biomol Sci Sydney NSW 2109 Australia Macquarie Univ Biotechnol Res Inst Sydney NSW 2109 Australia

Background: Pemphigus vulgaris (PV) is a severe autoimmune blistering skin disorder that is strongly associated with major histocompatibility complex class II alleles DRBI*0402 and DQBI*0503. The target antigen of PV, desmoglein 3 (Dsg3), is crucial for initiating T-cell response in early disease. Although a number of T-cell specificities within Dsg3 have been reported, the number is limited and the role of T-cells in the pathogenesis of PV remains poorly understood. We report here a structure-based model for the prediction of peptide binding to DRBI*0402 and DQBI*0503. The scoring functions were rigorously trained, tested and validated using experimentally verified peptide sequences. Results: High predictivity is obtained for both DRBI*0402 (r(2) = 0.90, s = 1.20 kJ/mol, q(2) = 0.82, s(press) = 1.61 kJ/mol) and DQBI*0503 (r(2) = 0.95, s = 1.20 kJ/mol, q(2) = 0.75, s(press) = 2.15 kJ/mol) models, compared to experimental data. We investigated the binding patterns of Dsg3 peptides and illustrate the existence of multiple immunodominant epitopes that may be responsible for both disease initiation and propagation in PV. Further analysis reveals that DRBI*0402 and DQBI*0503 may share similar specificities by binding peptides at different binding registers, thus providing a molecular mechanism for the dual HLA association observed in PV. Conclusion: Collectively, the results of this study provide interesting new insights into the pathology of PV. This is the first report illustrating high-level of cross-reactivity between both PV-implicated alleles, DRBI*0402 and DQBI*0503, as well as the existence of a potentially large number of T-cell epitopes throughout the entire Dsg3 extracellular domain (ECD) and transmembrane region. Our results reveal that DR4 and DR6 PV may initiate in the ECD and transmembrane region respectively, with implications for immunotherapeutic strategies for the treatment of this autoimmune disease.

关键词： Major Histocompatibility Complex Transmembrane Region protein data bank code Experimental IC50 Disease Initiation

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