When studying multi-body protein complexes, biochemists use computational tools that can suggest hundreds or thousands of their possible spatial configurations. However, it is not feasible to experimentally verify more than only a very small subset of them. In this paper, we propose a novel multiscale visual drilldown approach that was designed in tight collaboration with proteomic experts, enabling a systematic exploration of the configuration space. Our approach takes advantage of the hierarchical structure of the data -- from the whole ensemble of protein complex configurations to the individual configurations, their contact interfaces, and the interacting amino acids. Our new solution is based on interactively linked 2D and 3D views for individual hierarchy levels and at each level, we offer a set of selection and filtering operations enabling the user to narrow down the number of configurations that need to be manually scrutinized. Furthermore, we offer a dedicated filter interface, which provides the users with an overview of the applied filtering operations and enables them to examine their impact on the explored ensemble. This way, we maintain the history of the exploration process and thus enable the user to return to an earlier point of the exploration. We demonstrate the effectiveness of our approach on two case studies conducted by collaborating proteomic experts.
One of the first tools designed primarily for multi-body docking was CombDock @cite_10 . The algorithm works on a principle of hierarchical construction of the complex from smaller subunits and a greedy selection of the best-ranking subunits. The combinatorial step is followed by the reduction of solutions based on RMSD and a scoring function. Multi--LZerD @cite_24 uses a genetic algorithm to generate complexes from initial pairwise docks and applies an energy minimization structure refinement procedure for the ranking of the solutions. @cite_13 proposed an ant colony optimization approach to solve the combinatorial problem. DockStar @cite_33 formulates the task of detecting the spatial conformation of a protein complex as an Integer Linear Program. Unlike other methods, it also integrates experimental data from mass spectrometry into the scoring of the solutions. Another tool reusing pairwise docks in combination with experimental data is PRISM-EM @cite_14 . It uses density maps from cryo-electron microscopy for guiding the placement of subunits.
@cite_13 @cite_14 @cite_33 @cite_24 @cite_10
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The majority of proteins function when associated in multimolecular assemblies. Yet, prediction of the structures of multimolecular complexes has largely not been addressed, probably due to the magnitude of the combinatorial complexity of the problem. Docking applications have traditionally been used to predict pairwise interactions between molecules. We have developed an algorithm that extends the application of docking to multimolecular assemblies. We apply it to predict quaternary structures of both oligomers and multi-protein complexes. The algorithm predicted well a near-native arrangement of the input subunits for all cases in our data set, where the number of the subunits of the different target complexes varied from three to ten. In order to simulate a more realistic scenario, unbound cases were tested. In these cases the input conformations of the subunits are either unbound conformations of the subunits or a model obtained by a homology modeling technique. The successful predictions of the unbound cases, where the input conformations of the subunits are different from their conformations within the target complex, suggest that the algorithm is robust. We expect that this type of algorithm should be particularly useful to predict the structures of large macromolecular assemblies, which are difficult to solve by experimental structure determination. The tertiary structures of protein complexes provide a crucial insight about the molecular mechanisms that regulate their functions and assembly. However, solving protein complex structures by experimental methods is often more difficult than single protein structures. Here, we have developed a novel computational multiple protein docking algorithm, Multi-LZerD, that builds models of multimeric complexes by effectively reusing pairwise docking predictions of component proteins. A genetic algorithm is applied to explore the conformational space followed by a structure refinement procedure. Benchmark on eleven hetero-multimeric complexes resulted in near native conformations for all but one of them (a root mean square deviation smaller than 2.5A). We also show that our method copes with unbound docking cases well, outperforming the methodology that can be directly compared to our approach. Multi-LZerD was able to predict near native structures for multimeric complexes of various topologies. Mitochondria have specialized ribosomes that have diverged from their bacterial and cytoplasmic counterparts. We have solved the structure of the yeast mitoribosomal large subunit using single-particle cryo–electron microscopy. The resolution of 3.2 angstroms enabled a nearly complete atomic model to be built de novo and refined, including 39 proteins, 13 of which are unique to mitochondria, as well as expansion segments of mitoribosomal RNA. The structure reveals a new exit tunnel path and architecture, unique elements of the E site, and a putative membrane docking site. Many biological processes are governed by large assemblies of protein molecules. However, it is often very difficult to determine the three-dimensional structures of these assemblies using experimental biophysical techniques. Hence there is a need to develop computational approaches to fill this gap. This article presents an ant colony optimization approach to predict the structure of large multi-component protein complexes. Starting from pair-wise docking predictions, a multi-graph consisting of vertices representing the component proteins and edges representing candidate interactions is constructed. This allows the assembly problem to be expressed in terms of searching for a minimum weight spanning tree. However, because the problem remains highly combinatorial, the search space cannot be enumerated exhaustively and therefore heuristic optimisation techniques must be used. The utility of the ant colony based approach is demonstrated by re-assembling known protein complexes from the Protein Data Bank. The algorithm is able to identify near-native solutions for five of the six cases tested. This demonstrates that the ant colony approach provides a useful way to deal with the highly combinatorial multi-component protein assembly problem. Background The development of accurate protein-protein docking programs is making this kind of simulations an effective tool to predict the 3D structure and the surface of interaction between the molecular partners in macromolecular complexes. However, correctly scoring multiple docking solutions is still an open problem. As a consequence, the accurate and tedious screening of many docking models is usually required in the analysis step. Consider a set of oligomers listing the subunits involved in sub-complexes of a macro-molecular assembly, obtained e.g. using native mass spectrometry or affinity purification. Given these oligomers, connectivity inference (CI) consists of finding the most plausible contacts between these subunits, and minimum connectivity inference (MCI) is the variant consisting of finding a set of contacts of smallest cardinality. MCI problems avoid speculating on the total number of contacts, but yield a subset of all contacts and do not allow exploiting a priori information on the likelihood of individual contacts. In this context, we present two novel algorithms, MILP-W and MILP-WB. The former solves the minimum weight connectivity inference (MWCI), an optimization problem whose criterion mixes the number of contacts and their likelihood. The latter uses the former in a bootstrap fashion, to improve the sensitivity and the specificity of solution sets. Experiments on three systems (yeast exosome, yeast proteasome lid, human eiF3), for which reference contacts are known (crystal structure, cryo electron microscopy, cross-linking), show that our algorithms predict contacts with high specificity and sensitivity, yielding a very significant improvement over previous work, typically a twofold increase in sensitivity. The software accompanying this paper is made available, and should prove of ubiquitous interest whenever connectivity inference from oligomers is faced. This article presents a method to study large-scale conformational changes by combining electron microscopy (EM) single-particle image analysis and normal mode analysis (NMA). It is referred to as HEMNMA, which stands for hybrid electron microscopy normal mode analysis. NMA of a reference structure (atomic-resolution structure or EM volume) is used to predict possible motions that are then confronted with EM images within an automatic iterative elastic 3D-to-2D alignment procedure to identify actual motions in the imaged samples. HEMNMA can be used to extensively analyze the conformational changes and may be used in combination with classic discrete procedures. The identified conformations allow modeling of deformation pathways compatible with the experimental data. HEMNMA was tested with synthetic and experimental data sets of E. coli 70S ribosome, DNA polymerase Pol a and B subunit complex of the eukaryotic primosome, and tomato bushy stunt virus. NNScore is a neural-network-based scoring function designed to aid the computational identification of small-molecule ligands. While the test cases included in the original NNScore article demonstrated the utility of the program, the application examples were limited. The purpose of the current work is to further confirm that neural-network scoring functions are effective, even when compared to the scoring functions of state-of-the-art docking programs, such as AutoDock, the most commonly cited program, and AutoDock Vina, thought to be two orders of magnitude faster. Aside from providing additional validation of the original NNScore function, we here present a second neural-network scoring function, NNScore 2.0. NNScore 2.0 considers many more binding characteristics when predicting affinity than does the original NNScore. The network output of NNScore 2.0 also differs from that of NNScore 1.0; rather than a binary classification of ligand potency, NNScore 2.0 provides a single estimate of the pKd. To fac... Abstract Documents in computer-readable form can be used to provide information about other documents, i.e. those they cite. To do this efficiently requires procedures for computer recognition of citing statements. This is not easy, especially for multi-sentence citing statements. Computer recognition procedures have been developed which are accurate to the following extent: 73 of the words in statements selected by computer procedures as being citing statements are words which are correctly attributable to the corresponding documents. The retrieval effectiveness of computer-recognized citing statements was tested in the following way. First, for eight retrieval requests in inorganiic chemistry, average recall by search of Chemical Abstracts Service indexing and Chemical Abstracts abstract text words was found to be 50 . Words from citing statements referring to the papers to be retrieved were then added to the index terms and abstract words as additional access points, and searching was repeated. Average recall increased to 70 . Only words from citing statements published within a year of the cited papers were used. The retrieval effect of citing statement words alone (published within a year) without index or abstract terms was the following: average recall was 40 . When just the words of the titles of the cited papers were added to those citing statement words, average recall increased to 50 . Purpose – The purpose of this paper is to suggest an alternative to the widely used Times Cited criterion for analysing citation networks. The approach involves taking account of the natures of the papers that cite a given paper, so as to differentiate between papers that attract the same number of citations.Design methodology approach – ArticleRank is an algorithm that has been derived from Google's PageRank algorithm to measure the influence of journal articles. ArticleRank is applied to two datasets – a citation network based on an early paper on webometrics, and a self‐citation network based on the 19 most cited papers in the Journal of Documentation – using citation data taken from the Web of Knowledge database.Findings – ArticleRank values provide a different ranking of a set of papers from that provided by the corresponding Times Cited values, and overcomes the inability of the latter to differentiate between papers with the same numbers of citations. The difference in rankings between Times Cited ... The molecular docking problem is to determine how molecules interact with other molecules and plays a key role in understanding how cells function. DockingShop is an integrated environment far interactively steering molecular docking by navigating a ligand or protein to the receptor's estimated binding site. This tool provides a graphical interface for molecular modeling featuring real-time visual guides, interactive manipulation, navigation, optimization, and dynamic visualization enabling users to apply their biological knowledge to steer the docking process. Person re-identification is a challenge in video-based surveillance where the goal is to identify the same person in different camera views. In recent years, many algorithms have been proposed that approach this problem by designing suitable feature representations for images of persons or by training appropriate distance metrics that learn to distinguish between images of different persons. Aggregating the results from multiple algorithms for person re-identification is a relatively less-explored area of research. In this paper, we formulate an algorithm that maps the ranking process in a person re-identification algorithm to a problem in graph theory. We then extend this formulation to allow for the use of results from multiple algorithms to make a consensus-based decision for the person re-identification problem. The algorithm is unsupervised and takes into account only the matching scores generated by multiple algorithms for creating a consensus of results. Further, we show how the graph theoretic problem can be solved by a two-step process. First, we obtain a rough estimate of the solution using a greedy algorithm. Then, we extend the construction of the proposed graph so that the problem can be efficiently solved by means of Ant Colony Optimization, a heuristic path-searching algorithm for complex graphs. While we present the algorithm in the context of person reidentification, it can potentially be applied to the general problem of ranking items based on a consensus of multiple sets of scores or metric values. Interaction testing (also called combinatorial testing) is an cost-effective test generation technique in software testing. Most research work focuses on finding effective approaches to build optimal t-way interaction test suites. However, the strength of different factor sets may not be consistent due to the practical test requirements. To solve this problem, a variable strength combinatorial object and several approaches based on it have been proposed. These approaches include simulated annealing (SA) and greedy algorithms. SA starts with a large randomly generated test suite and then uses a binary search process to find the optimal solution. Although this approach often generates the minimal test suites, it is time consuming. Greedy algorithms avoid this shortcoming but the size of generated test suites is usually not as small as SA. In this paper, we propose a novel approach to generate variable strength interaction test suites (VSITs). In our approach, we adopt a one-test-at-a-time strategy to build final test suites. To generate a single test, we adopt ant colony system (ACS) strategy, an effective variant of ant colony optimization (ACO). In order to successfully adopt ACS, we formulize the solution space, the cost function and several heuristic settings in this framework. We also apply our approach to some typical inputs. Experimental results show the effectiveness of our approach especially compared to greedy algorithms and several existing tools. A citing sentence is one that appears in a scientific article and cites previous work. Citing sentences have been studied and used in many applications. For example, they have been used in scientific paper summarization, automatic survey generation, paraphrase identification, and citation function classification. Citing sentences that cite multiple papers are common in scientific writing. This observation should be taken into consideration when using citing sentences in applications. For instance, when a citing sentence is used in a summary of a scientific paper, only the fragments of the sentence that are relevant to the summarized paper should be included in the summary. In this paper, we present and compare three different approaches for identifying the fragments of a citing sentence that are related to a given target reference. Our methods are: word classification, sequence labeling, and segment classification. Our experiments show that segment classification achieves the best results. Electron cryomicroscopy can yield near-atomic resolution structures of highly ordered macromolecular complexes. Often however some subunits bind in a flexible manner, have different symmetry from the rest of the complex, or are present in sub-stoichiometric amounts, limiting the attainable resolution. Here we report a general method for the localized three-dimensional reconstruction of such subunits. After determining the particle orientations, local areas corresponding to the subunits can be extracted and treated as single particles. We demonstrate the method using three examples including a flexible assembly and complexes harbouring subunits with either partial occupancy or mismatched symmetry. Most notably, the method allows accurate fitting of the monomeric RNA-dependent RNA polymerase bound at the threefold axis of symmetry inside a viral capsid, revealing for the first time its exact orientation and interactions with the capsid proteins. Localized reconstruction is expected to provide novel biological insights in a range of challenging biological systems. In this work, we address the problem of joint modeling of text and citations in the topic modeling framework. We present two different models called the Pairwise-Link-LDA and the Link-PLSA-LDA models. The Pairwise-Link-LDA model combines the ideas of LDA [4] and Mixed Membership Block Stochastic Models [1] and allows modeling arbitrary link structure. However, the model is computationally expensive, since it involves modeling the presence or absence of a citation (link) between every pair of documents. The second model solves this problem by assuming that the link structure is a bipartite graph. As the name indicates, Link-PLSA-LDA model combines the LDA and PLSA models into a single graphical model. Our experiments on a subset of Citeseer data show that both these models are able to predict unseen data better than the baseline model of Erosheva and Lafferty [8], by capturing the notion of topical similarity between the contents of the cited and citing documents. Our experiments on two different data sets on the link prediction task show that the Link-PLSA-LDA model performs the best on the citation prediction task, while also remaining highly scalable. In addition, we also present some interesting visualizations generated by each of the models. In this paper we investigate the segmentation of closed contours in sub-cellular data using a framework that primarily combines the pairwise affinity grouping principles with a graph partitioning contour searching approach. One salient problem that precluded the application of these methods to large scale segmentation problems is the onerous computational complexity required to generate comprehensive representations that include all pairwise relationships between all pixels in the input data. To compensate for this problem a practical solution is to reduce the complexity of the input data by applying an oversegmentation technique prior to the application of the computationally demanding strands of the segmentation process. This approach opens the opportunity to build specific shape and intensity models that can be successfully employed to extract the salient structures in the input image which are further processed to identify the cycles in an undirected graph. The proposed framework has been applied to the segmentation of mitochondria membranes in electron microscopy (EM) data which are characterized by low contrast and low signal to noise ratio. The algorithm has been quantitatively evaluated using two datasets where the segmentation results have been compared with the corresponding manual annotations. The performance of the proposed algorithm has been measured using standard metrics such as Precision and Recall and the experimental results indicate a high level of segmentation accuracy. Scholars are increasingly citing electronic “web references” which are not preserved in libraries or full text archives. WebCite is a new standard for citing web references. To “webcite” a document involves archiving the cited Web page through www.webcitation.org and citing the WebCite permalink instead of (or in addition to) the unstable live Web page. This journal has amended its “instructions for authors” accordingly, asking authors to archive cited Web pages before submitting a manuscript. Almost 200 other journals are already using the system. We discuss the rationale for WebCite, its technology, and how scholars, editors, and publishers can benefit from the service. Citing scholars initiate an archiving process of all cited Web references, ideally before they submit a manuscript. Authors of online documents and websites which are expected to be cited by others can ensure that their work is permanently available by creating an archived copy using WebCite and providing the citation information including the WebCite link on their Web document(s). Editors should ask their authors to cache all cited Web addresses (Uniform Resource Locators, or URLs) “prospectively” before submitting their manuscripts to their journal. Editors and publishers should also instruct their copyeditors to cache cited Web material if the author has not done so already. Finally, WebCite can process publisher submitted “citing articles” (submitted for example as eXtensible Markup Language [XML] documents) to automatically archive all cited Web pages shortly before or on publication. Finally, WebCite can act as a focussed crawler, caching retrospectively references of already published articles. Copyright issues are addressed by honouring respective Internet standards (robot exclusion files, no-cache and no-archive tags). Long-term preservation is ensured by agreements with libraries and digital preservation organizations. The resulting WebCite Index may also have applications for research assessment exercises, being able to measure the impact of Web services and published Web documents through access and Web citation metrics. @PARASPLIT [J Med Internet Res 2005;7(5):e60] Empirical scoring functions based on either molecular force fields or cheminformatics descriptors are widely used, in conjunction with molecular docking, during the early stages of drug discovery to predict potency and binding affinity of a drug-like molecule to a given target. These models require expert-level knowledge of physical chemistry and biology to be encoded as hand-tuned parameters or features rather than allowing the underlying model to select features in a data-driven procedure. Here, we develop a general 3-dimensional spatial convolution operation for learning atomic-level chemical interactions directly from atomic coordinates and demonstrate its application to structure-based bioactivity prediction. The atomic convolutional neural network is trained to predict the experimentally determined binding affinity of a protein-ligand complex by direct calculation of the energy associated with the complex, protein, and ligand given the crystal structure of the binding pose. Non-covalent interactions present in the complex that are absent in the protein-ligand sub-structures are identified and the model learns the interaction strength associated with these features. We test our model by predicting the binding free energy of a subset of protein-ligand complexes found in the PDBBind dataset and compare with state-of-the-art cheminformatics and machine learning-based approaches. We find that all methods achieve experimental accuracy and that atomic convolutional networks either outperform or perform competitively with the cheminformatics based methods. Unlike all previous protein-ligand prediction systems, atomic convolutional networks are end-to-end and fully-differentiable. They represent a new data-driven, physics-based deep learning model paradigm that offers a strong foundation for future improvements in structure-based bioactivity prediction. Protein–protein docking is attracting increasing attention in drug discovery research targeting protein–protein interactions, owing to its potential in predicting protein–protein interactions and identifying ‘hot spot’ residues at the protein–protein interface. Given the relative lack of information about binding sites and the fact that proteins are generally larger than ligand, the search algorithms and evaluation methods for protein–protein docking differ somewhat from those for protein–ligand docking and, hence, require different research strategies. Here, we review the basic concepts, principles and advances of current search strategies and evaluation methods for protein–protein docking. We also discuss the current challenges and limitations, as well as future directions, of established approaches.