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Motivation: High-resolution Hi-C contact matrices reveal the detailed three-dimensional architecture of the genome, but high-coverage experimental Hi-C data are expensive to generate. Simultaneously, chromatin structure analyses struggle with extremely sparse contact matrices. To address this problem, computational methods to enhance low-coverage contact matrices have been developed, but existing methods are largely based on resolution enhancement methods for natural images and hence often employ models that do not distinguish between biologically meaningful contacts, such as loops and other stochastic contacts., Results: We present Capricorn, a machine learning model for Hi-C resolution enhancement that incorporates small-scale chromatin features as additional views of the input Hi-C contact matrix and leverages a diffusion probability model backbone to generate a high-coverage matrix. We show that Capricorn outperforms the state of the art in a cross-cell-line setting, improving on existing methods by 17% in mean squared error and 26% in F1 score for chromatin loop identification from the generated high-coverage data. We also demonstrate that Capricorn performs well in the cross-chromosome setting and cross-chromosome, cross-cell-line setting, improving the downstream loop F1 score by 14% relative to existing methods. We further show that our multiview idea can also be used to improve several existing methods, HiCARN and HiCNN, indicating the wide applicability of this approach. Finally, we use DNA sequence to validate discovered loops and find that the fraction of CTCF-supported loops from Capricorn is similar to those identified from the high-coverage data. Capricorn is a powerful Hi-C resolution enhancement method that enables scientists to find chromatin features that cannot be identified in the low-coverage contact matrix., Availability and Implementation: Implementation of Capricorn and source code for reproducing all figures in this paper are available at https://github.com/CHNFTQ/Capricorn., (© The Author(s) 2024. Published by Oxford University Press.)

Motivation: Analyzing large-scale single-cell transcriptomic datasets generated using different technologies is challenging due to the presence of batch-specific systematic variations known as batch effects. Since biological and technological differences are often interspersed, detecting and accounting for batch effects in RNA-seq datasets are critical for effective data integration and interpretation. Low-dimensional embeddings, such as principal component analysis (PCA) are widely used in visual inspection and estimation of batch effects. Linear dimensionality reduction methods like PCA are effective in assessing the presence of batch effects, especially when batch effects exhibit linear patterns. However, batch effects are inherently complex and existing linear dimensionality reduction methods could be inadequate and imprecise in the presence of sophisticated nonlinear batch effects., Results: We present Batch Effect Estimation using Nonlinear Embedding (BEENE), a deep nonlinear auto-encoder network which is specially tailored to generate an alternative lower dimensional embedding suitable for both linear and nonlinear batch effects. BEENE simultaneously learns the batch and biological variables from RNA-seq data, resulting in an embedding that is more robust and sensitive than PCA embedding in terms of detecting and quantifying batch effects. BEENE was assessed on a collection of carefully controlled simulated datasets as well as biological datasets, including two technical replicates of mouse embryogenesis cells, peripheral blood mononuclear cells from three largely different experiments and five studies of pancreatic islet cells., Availability and Implementation: BEENE is freely available as an open source project at https://github.com/ashiq24/BEENE., (© The Author(s) 2023. Published by Oxford University Press.)

Motivation: The tertiary structures of an increasing number of biological macromolecules have been determined using cryo-electron microscopy (cryo-EM). However, there are still many cases where the resolution is not high enough to model the molecular structures with standard computational tools. If the resolution obtained is near the empirical borderline (3-4.5 Å), improvement in the map quality facilitates structure modeling., Results: We report EM-GAN, a novel approach that modifies an input cryo-EM map to assist protein structure modeling. The method uses a 3D generative adversarial network (GAN) that has been trained on high- and low-resolution density maps to learn the density patterns, and modifies the input map to enhance its suitability for modeling. The method was tested extensively on a dataset of 65 EM maps in the resolution range of 3-6 Å and showed substantial improvements in structure modeling using popular protein structure modeling tools., Availability and Implementation: https://github.com/kiharalab/EM-GAN, Google Colab: https://tinyurl.com/3ccxpttx., (© The Author(s) 2023. Published by Oxford University Press.)

Motivation: Rapidly generated scRNA-seq datasets enable us to understand cellular differences and the function of each individual cell at single-cell resolution. Cell-type classification, which aims at characterizing and labeling groups of cells according to their gene expression, is one of the most important steps for single-cell analysis. To facilitate the manual curation process, supervised learning methods have been used to automatically classify cells. Most of the existing supervised learning approaches only utilize annotated cells in the training step while ignoring the more abundant unannotated cells. In this article, we proposed scPretrain, a multi-task self-supervised learning approach that jointly considers annotated and unannotated cells for cell-type classification. scPretrain consists of a pre-training step and a fine-tuning step. In the pre-training step, scPretrain uses a multi-task learning framework to train a feature extraction encoder based on each dataset's pseudo-labels, where only unannotated cells are used. In the fine-tuning step, scPretrain fine-tunes this feature extraction encoder using the limited annotated cells in a new dataset., Results: We evaluated scPretrain on 60 diverse datasets from different technologies, species and organs, and obtained a significant improvement on both cell-type classification and cell clustering. Moreover, the representations obtained by scPretrain in the pre-training step also enhanced the performance of conventional classifiers, such as random forest, logistic regression and support-vector machines. scPretrain is able to effectively utilize the massive amount of unlabeled data and be applied to annotating increasingly generated scRNA-seq datasets., Availability and Implementation: The data and code underlying this article are available in scPretrain: Multi-task self-supervised learning for cell type classification, at https://github.com/ruiyi-zhang/scPretrain and https://zenodo.org/record/5802306., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motivation: Protein structure prediction remains as one of the most important problems in computational biology and biophysics. In the past few years, protein residue-residue contact prediction has undergone substantial improvement, which has made it a critical driving force for successful protein structure prediction. Boosting the accuracy of contact predictions has, therefore, become the forefront of protein structure prediction., Results: We show a novel contact map refinement method, ContactGAN, which uses Generative Adversarial Networks (GAN). ContactGAN was able to make a significant improvement over predictions made by recent contact prediction methods when tested on three datasets including protein structure modeling targets in CASP13 and CASP14. We show improvement of precision in contact prediction, which translated into improvement in the accuracy of protein tertiary structure models. On the other hand, observed improvement over trRosetta was relatively small, reasons for which are discussed. ContactGAN will be a valuable addition in the structure prediction pipeline to achieve an extra gain in contact prediction accuracy., Availability and Implementation: https://github.com/kiharalab/ContactGAN., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motivation: Many important cellular processes involve physical interactions of proteins. Therefore, determining protein quaternary structures provide critical insights for understanding molecular mechanisms of functions of the complexes. To complement experimental methods, many computational methods have been developed to predict structures of protein complexes. One of the challenges in computational protein complex structure prediction is to identify near-native models from a large pool of generated models., Results: We developed a convolutional deep neural network-based approach named DOcking decoy selection with Voxel-based deep neural nEtwork (DOVE) for evaluating protein docking models. To evaluate a protein docking model, DOVE scans the protein-protein interface of the model with a 3D voxel and considers atomic interaction types and their energetic contributions as input features applied to the neural network. The deep learning models were trained and validated on docking models available in the ZDock and DockGround databases. Among the different combinations of features tested, almost all outperformed existing scoring functions., Availability and Implementation: Codes available at http://github.com/kiharalab/DOVE, http://kiharalab.org/dove/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motivation: Precision medicine is an emerging field with hopes to improve patient treatment and reduce morbidity and mortality. To these ends, computational approaches have predicted associations among genes, chemicals and diseases. Such efforts, however, were often limited to using just some available association types. This lowers prediction coverage and, since prior evidence shows that integrating heterogeneous data is likely beneficial, it may limit accuracy. Therefore, we systematically tested whether using more association types improves prediction., Results: We study multimodal networks linking diseases, genes and chemicals (drugs) by applying three diffusion algorithms and varying information content. Ten-fold cross-validation shows that these networks are internally consistent, both within and across association types. Also, diffusion methods recovered missing edges, even if all the edges from an entire mode of association were removed. This suggests that information is transferable between these association types. As a realistic validation, time-stamped experiments simulated the predictions of future associations based solely on information known prior to a given date. The results show that many future published results are predictable from current associations. Moreover, in most cases, using more association types increases prediction coverage without significantly decreasing sensitivity and specificity. In case studies, literature-supported validation shows that these predictions mimic human-formulated hypotheses. Overall, this study suggests that diffusion over a more comprehensive multimodal network will generate more useful hypotheses of associations among diseases, genes and chemicals, which may guide the development of precision therapies., Availability and Implementation: Code and data are available at https://github.com/LichtargeLab/multimodal-network-diffusion., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motivation: Biological experiments including proteomics and transcriptomics approaches often reveal sets of proteins that are most likely to be involved in a disease/disorder. To understand the functional nature of a set of proteins, it is important to capture the function of the proteins as a group, even in cases where function of individual proteins is not known. In this work, we propose a model that takes groups of proteins found to work together in a certain biological context, integrates them into functional relevance networks, and subsequently employs an iterative inference on graphical models to identify group functions of the proteins, which are then extended to predict function of individual proteins., Results: The proposed algorithm, iterative group function prediction (iGFP), depicts proteins as a graph that represents functional relevance of proteins considering their known functional, proteomics and transcriptional features. Proteins in the graph will be clustered into groups by their mutual functional relevance, which is iteratively updated using a probabilistic graphical model, the conditional random field. iGFP showed robust accuracy even when substantial amount of GO annotations were missing. The perspective of 'group' function annotation opens up novel approaches for understanding functional nature of proteins in biological systems.Availability and implementation: http://kiharalab.org/iGFP/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motivation: Function annotation of proteins is fundamental in contemporary biology across fields including genomics, molecular biology, biochemistry, systems biology and bioinformatics. Function prediction is indispensable in providing clues for interpreting omics-scale data as well as in assisting biologists to build hypotheses for designing experiments. As sequencing genomes is now routine due to the rapid advancement of sequencing technologies, computational protein function prediction methods have become increasingly important. A conventional method of annotating a protein sequence is to transfer functions from top hits of a homology search; however, this approach has substantial short comings including a low coverage in genome annotation., Results: Here we have developed Phylo-PFP, a new sequence-based protein function prediction method, which mines functional information from a broad range of similar sequences, including those with a low sequence similarity identified by a PSI-BLAST search. To evaluate functional similarity between identified sequences and the query protein more accurately, Phylo-PFP reranks retrieved sequences by considering their phylogenetic distance. Compared to the Phylo-PFP's predecessor, PFP, which was among the top ranked methods in the second round of the Critical Assessment of Functional Annotation (CAFA2), Phylo-PFP demonstrated substantial improvement in prediction accuracy. Phylo-PFP was further shown to outperform prediction programs to date that were ranked top in CAFA2., Availability and Implementation: Phylo-PFP web server is available for at http://kiharalab.org/phylo_pfp.php., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motivation: Moonlighting proteins (MPs) are an important class of proteins that perform more than one independent cellular function. MPs are gaining more attention in recent years as they are found to play important roles in various systems including disease developments. MPs also have a significant impact in computational function prediction and annotation in databases. Currently MPs are not labeled as such in biological databases even in cases where multiple distinct functions are known for the proteins. In this work, we propose a novel method named DextMP, which predicts whether a protein is a MP or not based on its textual features extracted from scientific literature and the UniProt database., Results: DextMP extracts three categories of textual information for a protein: titles, abstracts from literature, and function description in UniProt. Three language models were applied and compared: a state-of-the-art deep unsupervised learning algorithm along with two other language models of different types, Term Frequency-Inverse Document Frequency in the bag-of-words and Latent Dirichlet Allocation in the topic modeling category. Cross-validation results on a dataset of known MPs and non-MPs showed that DextMP successfully predicted MPs with over 91% accuracy with significant improvement over existing MP prediction methods. Lastly, we ran DextMP with the best performing language models and text-based feature combinations on three genomes, human, yeast and Xenopus laevis , and found that about 2.5-35% of the proteomes are potential MPs., Availability and Implementation: Code available at http://kiharalab.org/DextMP ., Contact: dkihara@purdue.edu., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Motivation: Diffusion-based network models are widely used for protein function prediction using protein network data and have been shown to outperform neighborhood-based and module-based methods. Recent studies have shown that integrating the hierarchical structure of the Gene Ontology (GO) data dramatically improves prediction accuracy. However, previous methods usually either used the GO hierarchy to refine the prediction results of multiple classifiers, or flattened the hierarchy into a function-function similarity kernel. No study has taken the GO hierarchy into account together with the protein network as a two-layer network model., Results: We first construct a Bi-relational graph (Birg) model comprised of both protein-protein association and function-function hierarchical networks. We then propose two diffusion-based methods, BirgRank and AptRank, both of which use PageRank to diffuse information on this two-layer graph model. BirgRank is a direct application of traditional PageRank with fixed decay parameters. In contrast, AptRank utilizes an adaptive diffusion mechanism to improve the performance of BirgRank. We evaluate the ability of both methods to predict protein function on yeast, fly and human protein datasets, and compare with four previous methods: GeneMANIA, TMC, ProteinRank and clusDCA. We design four different validation strategies: missing function prediction, de novo function prediction, guided function prediction and newly discovered function prediction to comprehensively evaluate predictability of all six methods. We find that both BirgRank and AptRank outperform the previous methods, especially in missing function prediction when using only 10% of the data for training., Availability and Implementation: The MATLAB code is available at https://github.rcac.purdue.edu/mgribsko/aptrank ., Contact: gribskov@purdue.edu., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Motivation: With the decreased cost of RNA-Seq, an increasing number of non-model organisms have been sequenced. Due to the lack of reference genomes, de novo transcriptome assembly is required. However, there is limited systematic research evaluating the quality of de novo transcriptome assemblies and how the assembly quality influences downstream analysis., Results: We used two authentic RNA-Seq datasets from Arabidopsis thaliana, and produced transcriptome assemblies using eight programs with a series of k-mer sizes (from 25 to 71), including BinPacker, Bridger, IDBA-tran, Oases-Velvet, SOAPdenovo-Trans, SSP, Trans-ABySS and Trinity. We measured the assembly quality in terms of reference genome base and gene coverage, transcriptome assembly base coverage, number of chimeras and number of recovered full-length transcripts. SOAPdenovo-Trans performed best in base coverage, while Trans-ABySS performed best in gene coverage and number of recovered full-length transcripts. In terms of chimeric sequences, BinPacker and Oases-Velvet were the worst, while IDBA-tran, SOAPdenovo-Trans, Trans-ABySS and Trinity produced fewer chimeras across all single k-mer assemblies. In differential gene expression analysis, about 70% of the significantly differentially expressed genes (DEG) were the same using reference genome and de novo assemblies. We further identify four reasons for the differences in significant DEG between reference genome and de novo transcriptome assemblies: incomplete annotation, exon level differences, transcript fragmentation and incorrect gene annotation, which we suggest that de novo assembly is beneficial even when a reference genome is available., Availability and Implementation: Software used in this study are publicly available at the authors' websites., Contact: gribskov@purdue.edu, Supplimentary Information: Supplementary data are available at Bioinformatics online.

Motivation: Comparing protein tertiary structures is a fundamental procedure in structural biology and protein bioinformatics. Structure comparison is important particularly for evaluating computational protein structure models. Most of the model structure evaluation methods perform rigid body superimposition of a structure model to its crystal structure and measure the difference of the corresponding residue or atom positions between them. However, these methods neglect intrinsic flexibility of proteins by treating the native structure as a rigid molecule. Because different parts of proteins have different levels of flexibility, for example, exposed loop regions are usually more flexible than the core region of a protein structure, disagreement of a model to the native needs to be evaluated differently depending on the flexibility of residues in a protein., Results: We propose a score named FlexScore for comparing protein structures that consider flexibility of each residue in the native state of proteins. Flexibility information may be extracted from experiments such as NMR or molecular dynamics simulation. FlexScore considers an ensemble of conformations of a protein described as a multivariate Gaussian distribution of atomic displacements and compares a query computational model with the ensemble. We compare FlexScore with other commonly used structure similarity scores over various examples. FlexScore agrees with experts' intuitive assessment of computational models and provides information of practical usefulness of models., Availability and Implementation: https://bitbucket.org/mjamroz/flexscore, Contact: dkihara@purdue.edu, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press.)

Motivation: Ligand binding is a key aspect of the function of many proteins. Thus, binding ligand prediction provides important insight in understanding the biological function of proteins. Binding ligand prediction is also useful for drug design and examining potential drug side effects., Results: We present a computational method named Patch-Surfer2.0, which predicts binding ligands for a protein pocket. By representing and comparing pockets at the level of small local surface patches that characterize physicochemical properties of the local regions, the method can identify binding pockets of the same ligand even if they do not share globally similar shapes. Properties of local patches are represented by an efficient mathematical representation, 3D Zernike Descriptor. Patch-Surfer2.0 has significant technical improvements over our previous prototype, which includes a new feature that captures approximate patch position with a geodesic distance histogram. Moreover, we constructed a large comprehensive database of ligand binding pockets that will be searched against by a query. The benchmark shows better performance of Patch-Surfer2.0 over existing methods., Availability and Implementation: http://kiharalab.org/patchsurfer2.0/ CONTACT: dkihara@purdue.edu, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Unlabelled: MSstats is an R package for statistical relative quantification of proteins and peptides in mass spectrometry-based proteomics. Version 2.0 of MSstats supports label-free and label-based experimental workflows and data-dependent, targeted and data-independent spectral acquisition. It takes as input identified and quantified spectral peaks, and outputs a list of differentially abundant peptides or proteins, or summaries of peptide or protein relative abundance. MSstats relies on a flexible family of linear mixed models., Availability and Implementation: The code, the documentation and example datasets are available open-source at www.msstats.org under the Artistic-2.0 license. The package can be downloaded from www.msstats.org or from Bioconductor www.bioconductor.org and used in an R command line workflow. The package can also be accessed as an external tool in Skyline (Broudy et al., 2014) and used via graphical user interface., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Motivation: Importance of accurate automatic protein function prediction is ever increasing in the face of a large number of newly sequenced genomes and proteomics data that are awaiting biological interpretation. Conventional methods have focused on high sequence similarity-based annotation transfer which relies on the concept of homology. However, many cases have been reported that simple transfer of function from top hits of a homology search causes erroneous annotation. New methods are required to handle the sequence similarity in a more robust way to combine together signals from strongly and weakly similar proteins for effectively predicting function for unknown proteins with high reliability., Results: We present the extended similarity group (ESG) method, which performs iterative sequence database searches and annotates a query sequence with Gene Ontology terms. Each annotation is assigned with probability based on its relative similarity score with the multiple-level neighbors in the protein similarity graph. We will depict how the statistical framework of ESG improves the prediction accuracy by iteratively taking into account the neighborhood of query protein in the sequence similarity space. ESG outperforms conventional PSI-BLAST and the protein function prediction (PFP) algorithm. It is found that the iterative search is effective in capturing multiple-domains in a query protein, enabling accurately predicting several functions which originate from different domains., Availability: ESG web server is available for automated protein function prediction at http://dragon.bio.purdue.edu/ESG/.

Motivation: Extracting functional information from protein-protein interactions (PPI) poses significant challenges arising from the noisy, incomplete, generic and static nature of data obtained from high-throughput screening. Typical proteins are composed of multiple domains, often regarded as their primary functional and structural units. Motivated by these considerations, domain-domain interactions (DDI) for network-based analyses have received significant recent attention. This article performs a formal comparative investigation of the relationship between functional coherence and topological proximity in PPI and DDI networks. Our investigation provides the necessary basis for continued and focused investigation of DDIs as abstractions for functional characterization and modularization of networks., Results: We investigate the problem of assessing the functional coherence of two biomolecules (or segments thereof) in a formal framework. We establish essential attributes of admissible measures of functional coherence, and demonstrate that existing, well-accepted measures are ill-suited to comparative analyses involving different entities (i.e. domains versus proteins). We propose a statistically motivated functional similarity measure that takes into account functional specificity as well as the distribution of functional attributes across entity groups to assess functional similarity in a statistically meaningful and biologically interpretable manner. Results on diverse data, including high-throughput and computationally predicted PPIs, as well as structural and computationally inferred DDIs for different organisms show that: (i) the relationship between functional similarity and network proximity is captured in a much more (biologically) intuitive manner by our measure, compared to existing measures and (ii) network proximity and functional similarity are significantly more correlated in DDI networks than in PPI networks, and that structurally determined DDIs provide better functional relevance as compared to computationally inferred DDIs.

Motivation: Standardized annotations of biomolecules in interaction networks (e.g. Gene Ontology) provide comprehensive understanding of the function of individual molecules. Extending such annotations to pathways is a critical component of functional characterization of cellular signaling at the systems level., Results: We propose a framework for projecting gene regulatory networks onto the space of functional attributes using multigraph models, with the objective of deriving statistically significant pathway annotations. We first demonstrate that annotations of pairwise interactions do not generalize to indirect relationships between processes. Motivated by this result, we formalize the problem of identifying statistically overrepresented pathways of functional attributes. We establish the hardness of this problem by demonstrating the non-monotonicity of common statistical significance measures. We propose a statistical model that emphasizes the modularity of a pathway, evaluating its significance based on the coupling of its building blocks. We complement the statistical model by an efficient algorithm and software, Narada, for computing significant pathways in large regulatory networks. Comprehensive results from our methods applied to the Escherichia coli transcription network demonstrate that our approach is effective in identifying known, as well as novel biological pathway annotations., Availability: Narada is implemented in Java and is available at http://www.cs.purdue.edu/homes/jpandey/narada/.

Motivation: Backbone resonance assignment is a critical bottleneck in studies of protein structure, dynamics and interactions by nuclear magnetic resonance (NMR) spectroscopy. A minimalist approach to assignment, which we call 'contact-based', seeks to dramatically reduce experimental time and expense by replacing the standard suite of through-bond experiments with the through-space (nuclear Overhauser enhancement spectroscopy, NOESY) experiment. In the contact-based approach, spectral data are represented in a graph with vertices for putative residues (of unknown relation to the primary sequence) and edges for hypothesized NOESY interactions, such that observed spectral peaks could be explained if the residues were 'close enough'. Due to experimental ambiguity, several incorrect edges can be hypothesized for each spectral peak. An assignment is derived by identifying consistent patterns of edges (e.g. for alpha-helices and beta-sheets) within a graph and by mapping the vertices to the primary sequence. The key algorithmic challenge is to be able to uncover these patterns even when they are obscured by significant noise., Results: This paper develops, analyzes and applies a novel algorithm for the identification of polytopes representing consistent patterns of edges in a corrupted NOESY graph. Our randomized algorithm aggregates simplices into polytopes and fixes inconsistencies with simple local modifications, called rotations, that maintain most of the structure already uncovered. In characterizing the effects of experimental noise, we employ an NMR-specific random graph model in proving that our algorithm gives optimal performance in expected polynomial time, even when the input graph is significantly corrupted. We confirm this analysis in simulation studies with graphs corrupted by up to 500% noise. Finally, we demonstrate the practical application of the algorithm on several experimental beta-sheet datasets. Our approach is able to eliminate a large majority of noise edges and to uncover large consistent sets of interactions., Availability: Our algorithm has been implemented in the platform-independent Python code. The software can be freely obtained for academic use by request from the authors.