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1.
An efficient 'soft docking' algorithm is described to assist the prediction of protein-protein association using three-dimensional structures of molecules. The basic tools are the 'simplified protein' model and the docking algorithm of Wodak and Janin. The side chain flexibility of Arg, Lys, Asp, Glu and Met residues at the protein surface is taken into account. The complex type-dependent filtering technique on the basis of the geometric matching, hydrophobicity and electrostatic complementarity is used to select candidate binding modes. Subsequently, we calculate a scoring function which includes electrostatic and desolvation energy terms. In the 44 complexes tested including enzyme-inhibitor, antibody-antigen and other complexes, native-like structures were all found, of which 30 were ranked in the top 20. Thus, our soft docking algorithm has the potential to predict protein-protein recognition. 相似文献
2.
Background
Structure-based computational methods are needed to help identify and characterize protein-protein complexes and their function. For individual proteins, the most successful technique is homology modelling. We investigate a simple extension of this technique to protein-protein complexes. We consider a large set of complexes of known structures, involving pairs of single-domain proteins. The complexes are compared with each other to establish their sequence and structural similarities and the relation between the two. Compared to earlier studies, a simpler dataset, a simpler structural alignment procedure, and an additional energy criterion are used. Next, we compare the Xray structures to models obtained by threading the native sequence onto other, homologous complexes. An elementary requirement for a successful energy function is to rank the native structure above any threaded structure. We use the DFIRE β energy function, whose quality and complexity are typical of the models used today. Finally, we compare near-native models to distinctly non-native models. 相似文献3.
We investigate the extent to which the conformational fluctuations of proteins in solution reflect the conformational changes that they undergo when they form binary protein-protein complexes. To do this, we study a set of 41 proteins that form such complexes and whose three-dimensional structures are known, both bound in the complex and unbound. We carry out molecular dynamics simulations of each protein, starting from the unbound structure, and analyze the resulting conformational fluctuations in trajectories of 5 ns in length, comparing with the structure in the complex. It is found that fluctuations take some parts of the molecules into regions of conformational space close to the bound state (or give information about it), but at no point in the simulation does each protein as whole sample the complete bound state. Subsequent use of conformations from a clustered MD ensemble in rigid-body docking is nevertheless partially successful when compared to docking the unbound conformations, as long as the unbound conformations are themselves included with the MD conformations and the whole globally rescored. For one key example where sub-domain motion is present, a ribonuclease inhibitor, principal components analysis of the MD was applied and was also able to produce conformations for docking that gave enhanced results compared to the unbound. The most significant finding is that core interface residues show a tendency to be less mobile (by size of fluctuation or entropy) than the rest of the surface even when the other binding partner is absent, and conversely the peripheral interface residues are more mobile. This surprising result, consistent across up to 40 of the 41 proteins, suggests different roles for these regions in protein recognition and binding, and suggests ways that docking algorithms could be improved by treating these regions differently in the docking process. 相似文献
4.
With the accumulation of protein and its related data on the Internet, many domain-based computational techniques to predict protein interactions have been developed. However, most techniques still have many limitations when used in real fields. They usually suffer from low accuracy in prediction and do not provide any interaction possibility ranking method for multiple protein pairs. In this paper, we propose a probabilistic framework to predict the interaction probability of proteins and develop an interaction possibility ranking method for multiple protein pairs. Using the ranking method, one can discern the protein pairs that are more likely to interact with each other in multiple protein pairs. The validity of the prediction model was evaluated using an interacting set of protein pairs in yeast and an artificially generated non-interacting set of protein pairs. When 80% of the set of interacting protein pairs in the DIP (Database of Interacting Proteins) was used as a learning set of interacting protein pairs, high sensitivity (77%) and specificity (95%) were achieved for the test groups containing common domains with the learning set of proteins within our framework. The stability of the prediction model was also evident when tested over DIP CORE, HMS-PCI and TAP data. In the validation of the ranking method, we reveal that some correlations exist between the interacting probability and the accuracy of the prediction. 相似文献
5.
Xiaofeng Liu Fang Bai Sisheng Ouyang Xicheng Wang Honglin Li Hualiang Jiang 《BMC bioinformatics》2009,10(1):101-14
Background
Conformation generation is a ubiquitous problem in molecule modelling. Many applications require sampling the broad molecular conformational space or perceiving the bioactive conformers to ensure success. Numerous in silico methods have been proposed in an attempt to resolve the problem, ranging from deterministic to non-deterministic and systemic to stochastic ones. In this work, we described an efficient conformation sampling method named Cyndi, which is based on multi-objective evolution algorithm. 相似文献6.
The combination of the wide availability of protein backbone and side-chain NMR chemical shifts with advances in understanding of their relationship to protein structure makes these parameters useful for the assessment of structural-dynamic protein models. A new chemical shift predictor (PPM) is introduced, which is solely based on physical?Cchemical contributions to the chemical shifts for both the protein backbone and methyl-bearing amino-acid side chains. To explicitly account for the effects of protein dynamics on chemical shifts, PPM was directly refined against 100?ns long molecular dynamics (MD) simulations of 35 proteins with known experimental NMR chemical shifts. It is found that the prediction of methyl-proton chemical shifts by PPM from MD ensembles is improved over other methods, while backbone C??, C??, C??, N, and HN chemical shifts are predicted at an accuracy comparable to the latest generation of chemical shift prediction programs. PPM is particularly suitable for the rapid evaluation of large protein conformational ensembles on their consistency with experimental NMR data and the possible improvement of protein force fields from chemical shifts. 相似文献
7.
Limited sampling of conformational space by the distance geometry algorithm: implications for structures generated from NMR data 总被引:1,自引:0,他引:1
Calculations with a metric matrix distance geometry algorithm were performed that show that the standard implementation of the algorithm generally samples a very limited region of conformational space. This problem is most severe when only a small amount of distance information is used as input for the algorithm. Control calculations were performed on linear peptides, disulfide-linked peptides, and a double-stranded DNA decamer where only distances defining the covalent structures of the molecules (as well as the hydrogen bonds for the base pairs in the DNA) were included as input. Since the distance geometry algorithm is commonly used to generate structures of biopolymers from distance data obtained from NMR experiments, simulations were performed on the small globular protein basic pancreatic trypsin inhibitor (BPTI) that mimic calculations performed with actual NMR data. The results on BPTI and on the control peptides indicate that the standard implementation of the algorithm has two main problems: first, that it generates extended structures; second, that it has a tendency to consistently produce similar structures instead of sampling all structures consistent with the input distance information. These results also show that use of a simple root-mean-square deviation for evaluating the quality of the structures generated from NMR data may not be generally appropriate. The main sources of these problems are identified, and our results indicate that the problems are not a fundamental property of the distance geometry algorithm but arise from the implementations presently used to generate structures from NMR data. Several possible methods for alleviating these problems are discussed. 相似文献
8.
Conformational changes on complex formation have been measured for 39 pairs of structures of complexed proteins and unbound equivalents, averaged over interface and non-interface regions and for individual residues. We evaluate their significance by comparison with the differences seen in 12 pairs of independently solved structures of identical proteins, and find that just over half have some substantial overall movement. Movements involve main chains as well as side chains, and large changes in the interface are closely involved with complex formation, while those of exposed non-interface residues are caused by flexibility and disorder. Interface movements in enzymes are similar in extent to those of inhibitors. All eight of the complexes (six enzyme-inhibitor and two antibody-antigen) that have structures of both components in an unbound form available show some significant interface movement. However, predictive docking is successful even when some of the largest changes occur. We note however that the situation may be different in systems other than the enzyme-inhibitors which dominate this study. Thus the general model is induced fit but, because there is only limited conformational change in many systems, recognition can be treated as lock and key to a first approximation. 相似文献
9.
POINT: a database for the prediction of protein-protein interactions based on the orthologous interactome 总被引:1,自引:0,他引:1
Huang TW Tien AC Huang WS Lee YC Peng CL Tseng HH Kao CY Huang CY 《Bioinformatics (Oxford, England)》2004,20(17):3273-3276
One possible path towards understanding the biological function of a target protein is through the discovery of how it interfaces within protein-protein interaction networks. The goal of this study was to create a virtual protein-protein interaction model using the concepts of orthologous conservation (or interologs) to elucidate the interacting networks of a particular target protein. POINT (the prediction of interactome database) is a functional database for the prediction of the human protein-protein interactome based on available orthologous interactome datasets. POINT integrates several publicly accessible databases, with emphasis placed on the extraction of a large quantity of mouse, fruit fly, worm and yeast protein-protein interactions datasets from the Database of Interacting Proteins (DIP), followed by conversion of them into a predicted human interactome. In addition, protein-protein interactions require both temporal synchronicity and precise spatial proximity. POINT therefore also incorporates correlated mRNA expression clusters obtained from cell cycle microarray databases and subcellular localization from Gene Ontology to further pinpoint the likelihood of biological relevance of each predicted interacting sets of protein partners. 相似文献
10.
Pooja Sharma D.K. Bhattacharyya J.K. Kalita 《Journal of Genetic Engineering and Biotechnology》2018,16(1):217-226
Protein complexes are known to play a major role in controlling cellular activity in a living being. Identifying complexes from raw protein protein interactions (PPIs) is an important area of research. Earlier work has been limited mostly to yeast. Such protein complex identification methods, when applied to large human PPIs often give poor performance. We introduce a novel method called CSC to detect protein complexes. The method is evaluated in terms of positive predictive value, sensitivity and accuracy using the datasets of the model organism, yeast and humans. CSC outperforms several other competing algorithms for both organisms. Further, we present a framework to establish the usefulness of CSC in analyzing the influence of a given disease gene in a complex topologically as well as biologically considering eight major association factors. 相似文献
11.
WAM: an improved algorithm for modelling antibodies on the WEB 总被引:5,自引:0,他引:5
12.
Modifying the DPClus algorithm for identifying protein complexes based on new topological structures 总被引:4,自引:0,他引:4
Background
Identification of protein complexes is crucial for understanding principles of cellular organization and functions. As the size of protein-protein interaction set increases, a general trend is to represent the interactions as a network and to develop effective algorithms to detect significant complexes in such networks. 相似文献13.
The Ni(II)-MDP-OH system (MDP=methylene diphosphonic acid) and stability constants of complexes formed at ionic strength 0.15M at 298K were established by direct current polarography (DCP) and glass electrode potentiometry (GEP). The final M-L-OH model could only be arrived to by employing recent concept of virtual potentiometry (VP). VP-data were generated from non-equilibrium and dynamic DC polarographic technique. The VP and GEP data were refined simultaneously by software dedicated to potentiometric studies of metal complexes. Species distribution diagrams that were generated for different experimental conditions employed in this work assisted in making the final choice regarding the metal-ligand model. The model established contains ML, ML(2), ML(OH) and ML(OH)(2) with stability constants, as logbeta, 7.94+/-0.02, 13.75+/-0.02, 12.04 (fixed value), and 16.75+/-0.05, respectively. It has been demonstrated that virtual potential must be used in modelling operations (predictions of species formed) when a polarographic signal decreases significantly due to the formation of polarographically inactive species (or formation of inert complexes). The linear free energy relationships that included stability constant logK(1) for Ni(II)-MDP established in this work together with other available data were used to predict logK(1) values for Sm(III) and Ho(III) with MDP. The logK(1) values for Sm(III)-MDP and Ho(III)-MDP were estimated to be 9.65+/-0.10 and 9.85+/-0.10, respectively. 相似文献
14.
IRECS: a new algorithm for the selection of most probable ensembles of side-chain conformations in protein models 总被引:2,自引:0,他引:2
Hartmann C Antes I Lengauer T 《Protein science : a publication of the Protein Society》2007,16(7):1294-1307
We introduce a new algorithm, IRECS (Iterative REduction of Conformational Space), for identifying ensembles of most probable side-chain conformations for homology modeling. On the basis of a given rotamer library, IRECS ranks all side-chain rotamers of a protein according to the probability with which each side chain adopts the respective rotamer conformation. This ranking enables the user to select small rotamer sets that are most likely to contain a near-native rotamer for each side chain. IRECS can therefore act as a fast heuristic alternative to the Dead-End-Elimination algorithm (DEE). In contrast to DEE, IRECS allows for the selection of rotamer subsets of arbitrary size, thus being able to define structure ensembles for a protein. We show that the selection of more than one rotamer per side chain is generally meaningful, since the selected rotamers represent the conformational space of flexible side chains. A knowledge-based statistical potential ROTA was constructed for the IRECS algorithm. The potential was optimized to discriminate between side-chain conformations of native and rotameric decoys of protein structures. By restricting the number of rotamers per side chain to one, IRECS can optimize side chains for a single conformation model. The average accuracy of IRECS for the chi1 and chi1+2 dihedral angles amounts to 84.7% and 71.6%, respectively, using a 40 degrees cutoff. When we compared IRECS with SCWRL and SCAP, the performance of IRECS was comparable to that of both methods. IRECS and the ROTA potential are available for download from the URL http://irecs.bioinf.mpi-inf.mpg.de. 相似文献
15.
Proteins with flexible binding surfaces can interact with numerous binding partners. However, this promiscuity is more difficult to understand in "rigid-body" proteins, whose binding results in little, or no, change in the position of backbone atoms. The binding of Kazal inhibitors to serine proteases is considered a classic case of rigid-body binding, although they bind to a wide range of proteases. We have studied the thermodynamics of binding of the Kazal serine protease inhibitor, turkey ovomucoid third domain (OMTKY3), to the serine protease subtilisin Carlsberg using isothermal titration calorimetry and have determined the crystal structure of the complex at very high resolution (1.1A). Comparison of the binding energetics and structure to other OMTKY3 interactions demonstrates that small changes in the position of side-chains can make significant contributions to the binding thermodynamics, including the enthalpy of binding. These effects emphasize that small, "rigid-body" proteins are still dynamic structures, and these dynamics make contributions to both the enthalpy and entropy of binding interactions. 相似文献
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18.
We present a reliable, simple, and quick system for screening antibody-antigen complexes on nitrocellulose. The apparatus necessary for this system is inexpensive and easy to use, and it can be adapted to blot or dot analysis without any modification. The number of antibody-antigen combinations that can be tested in one experiment ranges from 25 to 31 for blot analysis and from 345 to 600 for dot analysis. This system also offers numerous experimental advantages: it makes it possible to estimate with only one experiment the contribution of the different reaction stages to background noise and so allows unambiguous interpretation of the antibody-antigen reaction. Furthermore, this system can be used for any hybridization experiment on nitrocellulose. 相似文献
19.
Morozzo Della Rocca B Miniero DV Tasco G Dolce V Falconi M Ludovico A Cappello AR Sanchez P Stipani I Casadio R Desideri A Palmieri F 《Molecular membrane biology》2005,22(5):443-452
The structural and dynamic properties of the oxoglutarate carrier were investigated by introducing a single tryptophan in the Trp-devoid carrier in position 184, 190 or 199 and by monitoring the fluorescence spectra in the presence and absence of the substrate oxoglutarate. In the absence of substrate, the emission maxima of Arg190Trp, Cys184Trp and Leu199Trp are centered at 342, 345 and 348 nm, respectively, indicating that these residues have an increasing degree of solvent exposure. The emission intensity of the Arg190Trp and Cys184Trp mutants is higher than that of Leu199Trp. Addition of substrate increases the emission intensity of Leu199Trp, but not that of Cys184Trp and Arg190Trp. A 3D model of the oxoglutarate carrier was built using the structure of the ADP/ATP carrier as a template and was validated with the experimental results available in the literature. The model identifies Lys122 as the most likely candidate for the quenching of Trp199. Consistently, the double mutant Lys122Ala-Leu199Trp exhibits a higher emission intensity than Leu199Trp and does not display further fluorescence enhancement in response to substrate addition. Substitution of Lys122 with Cys and evaluation of its reactivity with a sulphydryl reagent in the presence and absence of substrate confirms that residue 122 is masked by the substrate, likely through a substrate-induced conformational change. 相似文献
20.
Blasco Morozzo Della Rocca Blasco Morozzo Della Rocca Daniela V. Miniero Gianluca Tasco Vincenza Dolce Mattia Falconi 《Molecular membrane biology》2013,30(5):443-452
The structural and dynamic properties of the oxoglutarate carrier were investigated by introducing a single tryptophan in the Trp-devoid carrier in position 184, 190 or 199 and by monitoring the fluorescence spectra in the presence and absence of the substrate oxoglutarate. In the absence of substrate, the emission maxima of Arg190Trp, Cys184Trp and Leu199Trp are centered at 342, 345 and 348 nm, respectively, indicating that these residues have an increasing degree of solvent exposure. The emission intensity of the Arg190Trp and Cys184Trp mutants is higher than that of Leu199Trp. Addition of substrate increases the emission intensity of Leu199Trp, but not that of Cys184Trp and Arg190Trp. A 3D model of the oxoglutarate carrier was built using the structure of the ADP/ATP carrier as a template and was validated with the experimental results available in the literature. The model identifies Lys122 as the most likely candidate for the quenching of Trp199. Consistently, the double mutant Lys122Ala-Leu199Trp exhibits a higher emission intensity than Leu199Trp and does not display further fluorescence enhancement in response to substrate addition. Substitution of Lys122 with Cys and evaluation of its reactivity with a sulphydryl reagent in the presence and absence of substrate confirms that residue 122 is masked by the substrate, likely through a substrate-induced conformational change. 相似文献