The computation of the global minimum energy conformation (GMEC) is an important and challenging topic in structure-based computational protein design. In this paper, we propose a new protein design algorithm based on the AND OR branch-and-bound (AOBB) search, which is a variant of the traditional branch-and-bound search algorithm, to solve this combinatorial optimization problem. By integrating with a powerful heuristic function, AOBB is able to fully exploit the graph structure of the underlying residue interaction network of a backbone template to significantly accelerate the design process. Tests on real protein data show that our new protein design algorithm is able to solve many prob- lems that were previously unsolvable by the traditional exact search algorithms, and for the problems that can be solved with traditional provable algorithms, our new method can provide a large speedup by several orders of magnitude while still guaranteeing to find the global minimum energy conformation (GMEC) solution.
The traditional BnB search algorithm @cite_0 usually ignores the underlying topological information of the residue interaction network constructed based on the backbone template, while AOBB is designed to exploit this property.
@cite_0
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Logarithmic search data structures, such as search trees and skiplists, are fundamental building blocks of many applications. Although the self-balancing binary search trees are among the most ubiquitous sequential search data structures, designing non-blocking rebalancing algorithms is challenging due to the required structural alternation, which may stall other concurrent operations. Skiplists, which probabilistically create multiple levels of shortcuts in an ordered list, provide practical alternatives to balanced search trees. The use of skiplists eliminates the need of rebalancing and ensures amortized logarithmic sequential search time, but concurrency is limited under write-dominated workload because the linkage between multiple distant nodes must be updated. In this paper, we present a linearizable lock-free dictionary design based on a multi-dimensional list (MDList). A node in an MDList arranges its child nodes by their dimensionality and order them by coordinate prefixes. The search operation works by first generating a one-to-one mapping from the scalar keys to a high-dimensional vectors space, then uniquely locating the target position by using the vector as coordinates. Our algorithm guarantees worst-case search time of O(log N) where N is the size of key space. Moreover, the ordering property of the data structure is readily maintained during mutations without rebalancing nor randomization. In our experimental evaluation using a micro-benchmark, our dictionary outperforms the state of the art approaches by as much as 100 when the key universe is large and an average of 30 across all scenarios. The nearestor near-neighbor query problems arise in a large variety of database applications, usually in the context of similarity searching. Of late, there has been increasing interest in building search index structures for performing similarity search over high-dimensional data, e.g., image databases, document collections, time-series databases, and genome databases. Unfortunately, all known techniques for solving this problem fall prey to the of dimensionality." That is, the data structures scale poorly with data dimensionality; in fact, if the number of dimensions exceeds 10 to 20, searching in k-d trees and related structures involves the inspection of a large fraction of the database, thereby doing no better than brute-force linear search. It has been suggested that since the selection of features and the choice of a distance metric in typical applications is rather heuristic, determining an approximate nearest neighbor should su ce for most practical purposes. In this paper, we examine a novel scheme for approximate similarity search based on hashing. The basic idea is to hash the points Supported by NAVY N00014-96-1-1221 grant and NSF Grant IIS-9811904. Supported by Stanford Graduate Fellowship and NSF NYI Award CCR-9357849. Supported by ARO MURI Grant DAAH04-96-1-0007, NSF Grant IIS-9811904, and NSF Young Investigator Award CCR9357849, with matching funds from IBM, Mitsubishi, Schlumberger Foundation, Shell Foundation, and Xerox Corporation. Permission to copy without fee all or part of this material is granted provided that the copies are not made or distributed for direct commercial advantage, the VLDB copyright notice and the title of the publication and its date appear, and notice is given that copying is by permission of the Very Large Data Base Endowment. To copy otherwise, or to republish, requires a fee and or special permission from the Endowment. Proceedings of the 25th VLDB Conference, Edinburgh, Scotland, 1999. from the database so as to ensure that the probability of collision is much higher for objects that are close to each other than for those that are far apart. We provide experimental evidence that our method gives signi cant improvement in running time over other methods for searching in highdimensional spaces based on hierarchical tree decomposition. Experimental results also indicate that our scheme scales well even for a relatively large number of dimensions (more than 50). A major challenge in molecular biology is reverse-engineering the cis-regulatory logic that plays a major role in the control of gene expression. This program includes searching through DNA sequences to identify “motifs” that serve as the binding sites for transcription factors or, more generally, are predictive of gene expression across cellular conditions. Several approaches have been proposed for de novo motif discovery–searching sequences without prior knowledge of binding sites or nucleotide patterns. However, unbiased validation is not straightforward. We consider two approaches to unbiased validation of discovered motifs: testing the statistical significance of a motif using a DNA “background” sequence model to represent the null hypothesis and measuring performance in predicting membership in gene clusters. We demonstrate that the background models typically used are “too null,” resulting in overly optimistic assessments of significance, and argue that performance in predicting TF binding or expression patterns from DNA motifs should be assessed by held-out data, as in predictive learning. Applying this criterion to common motif discovery methods resulted in universally poor performance, although there is a marked improvement when motifs are statistically significant against real background sequences. Moreover, on synthetic data where “ground truth” is known, discriminative performance of all algorithms is far below the theoretical upper bound, with pronounced “over-fitting” in training. A key conclusion from this work is that the failure of de novo discovery approaches to accurately identify motifs is basically due to statistical intractability resulting from the fixed size of co-regulated gene clusters, and thus such failures do not necessarily provide evidence that unfound motifs are not active biologically. Consequently, the use of prior knowledge to enhance motif discovery is not just advantageous but necessary. An implementation of the LR and ALR algorithms is available at http: code.google.com p likelihood-ratio-motifs . Nearest neighbor (NN) search in high dimensional space is an important problem in many applications. Ideally, a practical solution (i) should be implementable in a relational database, and (ii) its query cost should grow sub-linearly with the dataset size, regardless of the data and query distributions. Despite the bulk of NN literature, no solution fulfills both requirements, except locality sensitive hashing (LSH). The existing LSH implementations are either rigorous or adhoc. Rigorous-LSH ensures good quality of query results, but requires expensive space and query cost. Although adhoc-LSH is more efficient, it abandons quality control, i.e., the neighbor it outputs can be arbitrarily bad. As a result, currently no method is able to ensure both quality and efficiency simultaneously in practice. Motivated by this, we propose a new access method called the locality sensitive B-tree (LSB-tree) that enables fast high-dimensional NN search with excellent quality. The combination of several LSB-trees leads to a structure called the LSB-forest that ensures the same result quality as rigorous-LSH, but reduces its space and query cost dramatically. The LSB-forest also outperforms adhoc-LSH, even though the latter has no quality guarantee. Besides its appealing theoretical properties, the LSB-tree itself also serves as an effective index that consumes linear space, and supports efficient updates. Our extensive experiments confirm that the LSB-tree is faster than (i) the state of the art of exact NN search by two orders of magnitude, and (ii) the best (linear-space) method of approximate retrieval by an order of magnitude, and at the same time, returns neighbors with much better quality. A variety of functionally important protein properties, such as secondary structure, transmembrane topology and solvent accessibility, can be encoded as a labeling of amino acids. Indeed, the prediction of such properties from the primary amino acid sequence is one of the core projects of computational biology. Accordingly, a panoply of approaches have been developed for predicting such properties; however, most such approaches focus on solving a single task at a time. Motivated by recent, successful work in natural language processing, we propose to use multitask learning to train a single, joint model that exploits the dependencies among these various labeling tasks. We describe a deep neural network architecture that, given a protein sequence, outputs a host of predicted local properties, including secondary structure, solvent accessibility, transmembrane topology, signal peptides and DNA-binding residues. The network is trained jointly on all these tasks in a supervised fashion, augmented with a novel form of semi-supervised learning in which the model is trained to distinguish between local patterns from natural and synthetic protein sequences. The task-independent architecture of the network obviates the need for task-specific feature engineering. We demonstrate that, for all of the tasks that we considered, our approach leads to statistically significant improvements in performance, relative to a single task neural network approach, and that the resulting model achieves state-of-the-art performance. We study embedded Binarized Neural Networks (eBNNs) with the aim of allowing current binarized neural networks (BNNs) in the literature to perform feedforward inference efficiently on small embedded devices. We focus on minimizing the required memory footprint, given that these devices often have memory as small as tens of kilobytes (KB). Beyond minimizing the memory required to store weights, as in a BNN, we show that it is essential to minimize the memory used for temporaries which hold intermediate results between layers in feedforward inference. To accomplish this, eBNN reorders the computation of inference while preserving the original BNN structure, and uses just a single floating-point temporary for the entire neural network. All intermediate results from a layer are stored as binary values, as opposed to floating-points used in current BNN implementations, leading to a 32x reduction in required temporary space. We provide empirical evidence that our proposed eBNN approach allows efficient inference (10s of ms) on devices with severely limited memory (10s of KB). For example, eBNN achieves 95 accuracy on the MNIST dataset running on an Intel Curie with only 15 KB of usable memory with an inference runtime of under 50 ms per sample. To ease the development of applications in embedded contexts, we make our source code available that allows users to train and discover eBNN models for a learning task at hand, which fit within the memory constraint of the target device. Motivation: Inferring networks of proteins from biological data is a central issue of computational biology. Most network inference methods, including Bayesian networks, take unsupervised approaches in which the network is totally unknown in the beginning, and all the edges have to be predicted. A more realistic supervised framework, proposed recently, assumes that a substantial part of the network is known. We propose a new kernel-based method for supervised graph inference based on multiple types of biological datasets such as gene expression, phylogenetic profiles and amino acid sequences. Notably, our method assigns a weight to each type of dataset and thereby selects informative ones. Data selection is useful for reducing data collection costs. For example, when a similar network inference problem must be solved for other organisms, the dataset excluded by our algorithm need not be collected. Results: First, we formulate supervised network inference as a kernel matrix completion problem, where the inference of edges boils down to estimation of missing entries of a kernel matrix. Then, an expectation--maximization algorithm is proposed to simultaneously infer the missing entries of the kernel matrix and the weights of multiple datasets. By introducing the weights, we can integrate multiple datasets selectively and thereby exclude irrelevant and noisy datasets. Our approach is favorably tested in two biological networks: a metabolic network and a protein interaction network. Availability: Software is available on request. Contact: kato-tsuyoshi@aist.go.jp Supplementary information: A supplementary report including mathematical details is available at www.cbrc.jp kato faem faem.html We start a systematic study of data structures for the nearest colored node problem on trees. Given a tree with colored nodes and weighted edges, we want to answer queries (v,c) asking for the nearest node to node v that has color c. This is a natural generalization of the well-known nearest marked ancestor problem. We give an O(n)-space O(log log n)-query solution and show that this is optimal. We also consider the dynamic case where updates can change a node's color and show that in O(n) space we can support both updates and queries in O(log n) time. We complement this by showing that O(polylog n) update time implies Omega(log n log log n) query time. Finally, we consider the case where updates can change the edges of the tree (link-cut operations). There is a known (top-tree based) solution that requires update time that is roughly linear in the number of colors. We show that this solution is probably optimal by showing that a strictly sublinear update time implies a strictly subcubic time algorithm for the classical all pairs shortest paths problem on a general graph. We also consider versions where the tree is rooted, and the query asks for the nearest ancestor descendant of node v that has color c, and present efficient data structures for both variants in the static and the dynamic setting. Important biological information is encoded in the topology of biological networks. Comparative analyses of biological networks are proving to be valuable, as they can lead to transfer of knowledge between species and give deeper insights into biological function, disease, and evolution. We introduce a new method that uses the Hungarian algorithm to produce optimal global alignment between two networks using any cost function. We design a cost function based solely on network topology and use it in our network alignment. Our method can be applied to any two networks, not just biological ones, since it is based only on network topology. We use our new method to align protein-protein interaction networks of two eukaryotic species and demonstrate that our alignment exposes large and topologically complex regions of network similarity. At the same time, our alignment is biologically valid, since many of the aligned protein pairs perform the same biological function. From the alignment, we predict function of yet unannotated proteins, many of which we validate in the literature. Also, we apply our method to find topological similarities between metabolic networks of different species and build phylogenetic trees based on our network alignment score. The phylogenetic trees obtained in this way bear a striking resemblance to the ones obtained by sequence alignments. Our method detects topologically similar regions in large networks that are statistically significant. It does this independent of protein sequence or any other information external to network topology. Abstract We propose a novel approach to solving the approximate k-nearest neighbor search problem in metric spaces. The search structure is based on a navigable small world graph with vertices corresponding to the stored elements, edges to links between them, and a variation of greedy algorithm for searching. The navigable small world is created simply by keeping old Delaunay graph approximation links produced at the start of construction. The approach is very universal, defined in terms of arbitrary metric spaces and at the same time it is very simple. The algorithm handles insertions in the same way as queries: by finding approximate neighbors for the inserted element and connecting it to them. Both search and insertion can be done in parallel requiring only local information from the structure. The structure can be made distributed. The accuracy of the probabilistic k-nearest neighbor queries can be adjusted without rebuilding the structure. The performed simulation for data in the Euclidean spaces shows that the structure built using the proposed algorithm has small world navigation properties with log 2 ( n ) insertion and search complexity at fixed accuracy, and performs well at high dimensionality. Simulation on a CoPHiR dataset revealed its high efficiency in case of large datasets (more than an order of magnitude less metric computations at fixed recall) compared to permutation indexes. Only 0.03 of the 10 million 208-dimensional vector dataset is needed to be evaluated to achieve 0.999 recall (virtually exact search). For recall 0.93 processing speed 2800 queries s can be achieved on a dual Intel X5675 Xenon server node with Java implementation. The graph structure is a very important means to model schemaless data with complicated structures, such as protein-protein interaction networks, chemical compounds, knowledge query inferring systems, and road networks. This paper focuses on the index structure for similarity search on a set of large sparse graphs and proposes an efficient indexing mechanism by introducing the Q-Gram idea. By decomposing graphs to small grams (organized by κ-Adjacent Tree patterns) and pairing-up on those κ-Adjacent Tree patterns, the lower bound estimation of their edit distance can be calculated for candidate filtering. Furthermore, we have developed a series of techniques for inverted index construction and online query processing. By building the candidate set for the query graph before the exact edit distance calculation, the number of graphs need to proceed into exact matching can be greatly reduced. Extensive experiments on real and synthetic data sets have been conducted to show the effectiveness and efficiency of the proposed indexing mechanism. We have developed a web server (ProteinDBS) for the life science community to search for similar protein tertiary structures in real time. This system applies computer visualization techniques to extract the predominant visual patterns encoded in two-dimensional distance matrices generated from the three-dimensional coordinates of protein chains. When meaningful contents, represented in a multi-dimensional feature space, have been extracted from distance matrices, an advanced indexing structure, Entropy Balanced Statistical (EBS) k-d tree, is utilized to index the data. Our system is able to return search results in ranked order from a database with 46075 chains in seconds, exhibiting a reasonably high degree of precision. To our knowledge, this is the first real-time search engine for protein structure comparison. ProteinDBS provides two types of query method: query by Protein Data Bank protein chain ID and by new structures uploaded by users. The system is hosted at http: ProteinDBS.rnet.missouri.edu. Nearest Neighbor (NN) search in high-dimensional space is an important problem in many applications. From the database perspective, a good solution needs to have two properties: (i) it can be easily incorporated in a relational database, and (ii) its query cost should increase sublinearly with the dataset size, regardless of the data and query distributions. Locality-Sensitive Hashing (LSH) is a well-known methodology fulfilling both requirements, but its current implementations either incur expensive space and query cost, or abandon its theoretical guarantee on the quality of query results. Motivated by this, we improve LSH by proposing an access method called the Locality-Sensitive B-tree (LSB-tree) to enable fast, accurate, high-dimensional NN search in relational databases. The combination of several LSB-trees forms a LSB-forest that has strong quality guarantees, but improves dramatically the efficiency of the previous LSH implementation having the same guarantees. In practice, the LSB-tree itself is also an effective index which consumes linear space, supports efficient updates, and provides accurate query results. In our experiments, the LSB-tree was faster than: (i) iDistance (a famous technique for exact NN search) by two orders of magnitude, and (ii) MedRank (a recent approximate method with nontrivial quality guarantees) by one order of magnitude, and meanwhile returned much better results. As a second step, we extend our LSB technique to solve another classic problem, called Closest Pair (CP) search, in high-dimensional space. The long-term challenge for this problem has been to achieve subquadratic running time at very high dimensionalities, which fails most of the existing solutions. We show that, using a LSB-forest, CP search can be accomplished in (worst-case) time significantly lower than the quadratic complexity, yet still ensuring very good quality. In practice, accurate answers can be found using just two LSB-trees, thus giving a substantial reduction in the space and running time. In our experiments, our technique was faster: (i) than distance browsing (a well-known method for solving the problem exactly) by several orders of magnitude, and (ii) than D-shift (an approximate approach with theoretical guarantees in low-dimensional space) by one order of magnitude, and at the same time, outputs better results. We report the predictive all-atom folding of the 60 amino acid four-helix bacterial ribosomal protein (BRP) L20 with a stochastic evolutionary optimization method in a free-energy force field. The energetically best, as well as six of the 10 lowest conformations, converge to a near-native structure. All of the 10 best energy conformations share the secondary structure elements of the native conformation, but differ in their tertiary alignment. The best conformation has a backbone root-mean-square deviation of 4.6 A to the native conformation and reproduces most distance constraints of the NMR experiment to 1.5 A resolution. Starting from random initial conditions, the native content of the simulated population increases more than 60-fold in the course of the simulation. These data demonstrate the feasibility of predictive unbiased all-atom protein folding with present day computational resources for the BRP L20. We consider the problem of inferring the topology of an M-by-N network by sending probes between M sources and N receivers. Prior work has shown that this problem can be decomposed into two parts: first, infer smaller subnetwork components (i.e., 1-by-N's or 2-by-2's) and then merge these components to identify the M-by-N topology. In this paper, we focus on the second part. In particular, we assume that a 1by-N topology is given and that all 2-by-2 components can be queried and learned using end-to-end probes. The problem is which 2-by-2's to query and how to merge them with the 1-byN, so as to exactly identify the 2-by-N topology, and optimize a number of performance metrics including measurement traffic, time complexity, and memory usage. We provide a lower bound, ⌈N 2⌉, on the number of 2-by-2's required by any active learning algorithm and we also propose a greedy algorithm that is nearoptimal and efficient in practice. It follows a bottom-up approach: at every step, it selects two receivers, queries the corresponding 2-by-2, and merges it with the given 1-by-N. The algorithm requires exactly N - 1 steps, which is much less than all (N:2) possible 2-by-2's, and it correctly identifies the 2-by-N topology. Low-dimensional embeddings of nodes in large graphs have proved extremely useful in a variety of prediction tasks, from content recommendation to identifying protein functions. However, most existing approaches require that all nodes in the graph are present during training of the embeddings; these previous approaches are inherently transductive and do not naturally generalize to unseen nodes. Here we present GraphSAGE, a general, inductive framework that leverages node feature information (e.g., text attributes) to efficiently generate node embeddings. Instead of training individual embeddings for each node, we learn a function that generates embeddings by sampling and aggregating features from a node's local neighborhood. Our algorithm outperforms strong baselines on three inductive node-classification benchmarks: we classify the category of unseen nodes in evolving information graphs based on citation and Reddit post data, and we show that our algorithm generalizes to completely unseen graphs using a multi-graph dataset of protein-protein interactions. Recently there has been a surge of interest to use branch-and-bound (bnb) optimisation for 3D point cloud registration. While bnb guarantees globally optimal solutions, it is usually too slow to be practical. A fundamental source of difficulty is the search for the rotation parameters in the 3D rigid transform. In this work, assuming that the translation parameters are known, we focus on constructing a fast rotation search algorithm. With respect to an inherently robust geometric matching criterion, we propose a novel bounding function for bnb that allows rapid evaluation. Underpinning our bounding function is the usage of stereographic projections to precompute and spatially index all possible point matches. This yields a robust and global algorithm that is significantly faster than previous methods. To conduct full 3D registration, the translation can be supplied by 3D feature matching, or by another optimisation framework that provides the translation. On various challenging point clouds, including those taken out of lab settings, our approach demonstrates superior efficiency. In this paper, we propose a novel image indexing and retrieval algorithm using local tetra patterns (LTrPs) for content-based image retrieval (CBIR). The standard local binary pattern (LBP) and local ternary pattern (LTP) encode the relationship between the referenced pixel and its surrounding neighbors by computing gray-level difference. The proposed method encodes the relationship between the referenced pixel and its neighbors, based on the directions that are calculated using the first-order derivatives in vertical and horizontal directions. In addition, we propose a generic strategy to compute nth-order LTrP using (n - 1)th-order horizontal and vertical derivatives for efficient CBIR and analyze the effectiveness of our proposed algorithm by combining it with the Gabor transform. The performance of the proposed method is compared with the LBP, the local derivative patterns, and the LTP based on the results obtained using benchmark image databases viz., Corel 1000 database (DB1), Brodatz texture database (DB2), and MIT VisTex database (DB3). Performance analysis shows that the proposed method improves the retrieval result from 70.34 44.9 to 75.9 48.7 in terms of average precision average recall on database DB1, and from 79.97 to 85.30 and 82.23 to 90.02 in terms of average retrieval rate on databases DB2 and DB3, respectively, as compared with the standard LBP. While sensor networks are going to be deployed in diverse application specific contexts, one unifying view is to treat them essentially as distributed databases. The simplest mechanism to obtain information from this kind of a database is to flood queries for named data within the network and obtain the relevant responses from sources. However, if the queries are (a) complex, (b) one-shot, and (c) for replicated data, this simple approach can be highly inefficient. In the context of energy-starved sensor networks, alternative strategies need to be examined for such queries. We propose a novel and efficient mechanism for obtaining information in sensor networks which we refer to as ACtive QUery forwarding In sensoR nEtworks (ACQUIRE). The basic principle behind ACQUIRE is to consider the query as an active entity that is forwarded through the network (either randomly or in some directed manner) in search of the solution. ACQUIRE also incorporates a look-ahead parameter d in the following manner: intermediate nodes that handle the active query use information from all nodes within d hops in order to partially resolve the query. When the active query is fully resolved, a completed response is sent directly back to the querying node. We take a mathematical modelling approach in this paper to calculate the energy costs associated with ACQUIRE. The models permit us to characterize analytically the impact of critical parameters, and compare the performance of ACQUIRE with respect to other schemes such as flooding-based querying (FBQ) and expanding ring search (ERS), in terms of energy usage, response latency and storage requirements. We show that with optimal parameter settings, depending on the update frequency, ACQUIRE obtains order of magnitude reduction over FBQ and potentially over 60–75 reduction over ERS (in highly dynamic environments and high query rates) in consumed energy. We show that these energy savings are provided in trade for increased response latency. The mathematical analysis is validated through extensive simulations. � 2003 Elsevier B.V. All rights reserved. We present a fully dynamic randomized data structure that can answer queries about the convex hull of a set of n points in three dimensions, where insertions take O(log3n) expected amortized time, deletions take O(log6n) expected amortized time, and extreme-point queries take O(log2n) worst-case time. This is the first method that guarantees polylogarithmic update and query cost for arbitrary sequences of insertions and deletions, and improves the previous O(ne)-time method by Agarwal and Matousek a decade ago. As a consequence, we obtain similar results for nearest neighbor queries in two dimensions and improved results for numerous fundamental geometric problems (such as levels in three dimensions and dynamic Euclidean minimum spanning trees in the plane).