Prediction of protein-protein interaction types using association rule based classification

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Park et alBackground: Protein-protein interactions (PPI) can be classified according to their characteristics into, for example obligate or transient interactions. The identification and characterization of these PPI types may help in the functional annotation of new protein complexes and in the prediction of protein interaction partners by knowledge driven approaches. Results: This work addresses pattern discovery of the interaction sites for four different interaction types to characterize and uses them for the prediction of PPI types employing Association Rule Based Classification (ARBC) which includes association rule generation and posterior classification. We incorporated domain information from protein complexes in SCOP proteins and identified 354 domain-interaction sites. 14 interface properties were calculated from amino acid and secondary structure composition and then used to generate a set of association rules characterizing these domain-interaction sites employing the APRIORI algorithm. Our results regarding the classification of PPI types based on a set of discovered association rules shows that the discriminative ability of association rules can significantly impact on the prediction power of classification models. We also showed that the accuracy of the classification can be improved through the use of structural domain information and also the use of secondary structure content. Conclusion: The advantage of our approach is that we can extract biologically significant information from the interpretation of the discovered association rules in terms of understandability and interpretability of rules. A web application based on our method can be found at http://bioinfo.ssu.ac.kr/~shpark/picasso/SHP was supported by the Korea Research Foundation Grant funded by the Korean Government(KRF-2005-214-E00050). JAR has been supported by the Programme Alβan, the European Union Programme of High level Scholarships for Latin America, scholarship E04D034854CL. SK was supported by Soongsil University Research Fund

Automatic prediction of catalytic residues by modeling residue structural neighborhood

Background: Prediction of catalytic residues is a major step in characterizing the function of enzymes. In its simpler formulation, the problem can be cast into a binary classification task at the residue level, by predicting whether the residue is directly involved in the catalytic process. The task is quite hard also when structural information is available, due to the rather wide range of roles a functional residue can play and to the large imbalance between the number of catalytic and non-catalytic residues.Results: We developed an effective representation of structural information by modeling spherical regions around candidate residues, and extracting statistics on the properties of their content such as physico-chemical properties, atomic density, flexibility, presence of water molecules. We trained an SVM classifier combining our features with sequence-based information and previously developed 3D features, and compared its performance with the most recent state-of-the-art approaches on different benchmark datasets. We further analyzed the discriminant power of the information provided by the presence of heterogens in the residue neighborhood.Conclusions: Our structure-based method achieves consistent improvements on all tested datasets over both sequence-based and structure-based state-of-the-art approaches. Structural neighborhood information is shown to be responsible for such results, and predicting the presence of nearby heterogens seems to be a promising direction for further improvements.Journal ArticleResearch Support, N.I.H. Extramuralinfo:eu-repo/semantics/publishe

The loss and gain of functional amino acid residues is a common mechanism causing human inherited disease

Elucidating the precise molecular events altered by disease-causing genetic variants represents a major challenge in translational bioinformatics. To this end, many studies have investigated the structural and functional impact of amino acid substitutions. Most of these studies were however limited in scope to either individual molecular functions or were concerned with functional effects (e.g. deleterious vs. neutral) without specifically considering possible molecular alterations. The recent growth of structural, molecular and genetic data presents an opportunity for more comprehensive studies to consider the structural environment of a residue of interest, to hypothesize specific molecular effects of sequence variants and to statistically associate these effects with genetic disease. In this study, we analyzed data sets of disease-causing and putatively neutral human variants mapped to protein 3D structures as part of a systematic study of the loss and gain of various types of functional attribute potentially underlying pathogenic molecular alterations. We first propose a formal model to assess probabilistically function-impacting variants. We then develop an array of structure-based functional residue predictors, evaluate their performance, and use them to quantify the impact of disease-causing amino acid substitutions on catalytic activity, metal binding, macromolecular binding, ligand binding, allosteric regulation and post-translational modifications. We show that our methodology generates actionable biological hypotheses for up to 41% of disease-causing genetic variants mapped to protein structures suggesting that it can be reliably used to guide experimental validation. Our results suggest that a significant fraction of disease-causing human variants mapping to protein structures are function-altering both in the presence and absence of stability disruption

Structural Prediction of Protein–Protein Interactions by Docking: Application to Biomedical Problems

A huge amount of genetic information is available thanks to the recent advances in sequencing technologies and the larger computational capabilities, but the interpretation of such genetic data at phenotypic level remains elusive. One of the reasons is that proteins are not acting alone, but are specifically interacting with other proteins and biomolecules, forming intricate interaction networks that are essential for the majority of cell processes and pathological conditions. Thus, characterizing such interaction networks is an important step in understanding how information flows from gene to phenotype. Indeed, structural characterization of protein–protein interactions at atomic resolution has many applications in biomedicine, from diagnosis and vaccine design, to drug discovery. However, despite the advances of experimental structural determination, the number of interactions for which there is available structural data is still very small. In this context, a complementary approach is computational modeling of protein interactions by docking, which is usually composed of two major phases: (i) sampling of the possible binding modes between the interacting molecules and (ii) scoring for the identification of the correct orientations. In addition, prediction of interface and hot-spot residues is very useful in order to guide and interpret mutagenesis experiments, as well as to understand functional and mechanistic aspects of the interaction. Computational docking is already being applied to specific biomedical problems within the context of personalized medicine, for instance, helping to interpret pathological mutations involved in protein–protein interactions, or providing modeled structural data for drug discovery targeting protein–protein interactions.Spanish Ministry of Economy grant number BIO2016-79960-R; D.B.B. is supported by a predoctoral fellowship from CONACyT; M.R. is supported by an FPI fellowship from the Severo Ochoa program. We are grateful to the Joint BSC-CRG-IRB Programme in Computational Biology.Peer ReviewedPostprint (author's final draft

Common physical basis of macromolecule-binding sites in proteins

Protein–DNA/RNA/protein interactions play critical roles in many biological functions. Previous studies have focused on the different features characterizing the different macromolecule-binding sites and approaches to detect these sites. However, no common unique signature of these sites had been reported. Thus, this work aims to provide a ‘common’ principle dictating the location of the different macromolecule-binding sites founded upon fundamental principles of binding thermodynamics. To achieve this aim, a comprehensive set of structurally nonhomologous DNA-, RNA-, obligate protein- and nonobligate protein-binding proteins, both free and bound to their respective macromolecules, was created and a novel strategy for detecting clusters of residues with electrostatic or steric strain given the protein structure was developed. The results show that regardless of the macromolecule type, the binding strength and conformational changes upon binding, macromolecule-binding sites are energetically less stable than nonmacromolecule-binding sites. They also reveal new energetic features distinguishing DNA- from RNA-binding sites and obligate protein- from nonobligate protein-binding sites in both free/bound protein structures

Statistical Relational Learning for Proteomics: Function, Interactions and Evolution

In recent years, the field of Statistical Relational Learning (SRL) [1, 2] has produced new, powerful learning methods that are explicitly designed to solve complex problems, such as collective classification, multi-task learning and structured output prediction, which natively handle relational data, noise, and partial information. Statistical-relational methods rely on some First- Order Logic as a general, expressive formal language to encode both the data instances and the relations or constraints between them. The latter encode background knowledge on the problem domain, and are use to restrict or bias the model search space according to the instructions of domain experts. The new tools developed within SRL allow to revisit old computational biology problems in a less ad hoc fashion, and to tackle novel, more complex ones. Motivated by these developments, in this thesis we describe and discuss the application of SRL to three important biological problems, highlighting the advantages, discussing the trade-offs, and pointing out the open problems. In particular, in Chapter 3 we show how to jointly improve the outputs of multiple correlated predictors of protein features by means of a very gen- eral probabilistic-logical consistency layer. The logical layer — based on grounding-specific Markov Logic networks [3] — enforces a set of weighted first-order rules encoding biologically motivated constraints between the pre- dictions. The refiner then improves the raw predictions so that they least violate the constraints. Contrary to canonical methods for the prediction of protein features, which typically take predicted correlated features as in- puts to improve the output post facto, our method can jointly refine all predictions together, with potential gains in overall consistency. In order to showcase our method, we integrate three stand-alone predictors of corre- lated features, namely subcellular localization (Loctree[4]), disulfide bonding state (Disulfind[5]), and metal bonding state (MetalDetector[6]), in a way that takes into account the respective strengths and weaknesses. The ex- perimental results show that the refiner can improve the performance of the underlying predictors by removing rule violations. In addition, the proposed method is fully general, and could in principle be applied to an array of heterogeneous predictions without requiring any change to the underlying software. In Chapter 4 we consider the multi-level protein–protein interaction (PPI) prediction problem. In general, PPIs can be seen as a hierarchical process occurring at three related levels: proteins bind by means of specific domains, which in turn form interfaces through patches of residues. Detailed knowl- edge about which domains and residues are involved in a given interaction has extensive applications to biology, including better understanding of the bind- ing process and more efficient drug/enzyme design. We cast the prediction problem in terms of multi-task learning, with one task per level (proteins, domains and residues), and propose a machine learning method that collec- tively infers the binding state of all object pairs, at all levels, concurrently. Our method is based on Semantic Based Regularization (SBR) [7], a flexible and theoretically sound SRL framework that employs First-Order Logic con- straints to tie the learning tasks together. Contrarily to most current PPI prediction methods, which neither identify which regions of a protein actu- ally instantiate an interaction nor leverage the hierarchy of predictions, our method resolves the prediction problem up to residue level, enforcing con- sistent predictions between the hierarchy levels, and fruitfully exploits the hierarchical nature of the problem. We present numerical results showing that our method substantially outperforms the baseline in several experi- mental settings, indicating that our multi-level formulation can indeed lead to better predictions. Finally, in Chapter 5 we consider the problem of predicting drug-resistant protein mutations through a combination of Inductive Logic Programming [8, 9] and Statistical Relational Learning. In particular, we focus on viral pro- teins: viruses are typically characterized by high mutation rates, which allow them to quickly develop drug-resistant mutations. Mining relevant rules from mutation data can be extremely useful to understand the virus adaptation mechanism and to design drugs that effectively counter potentially resistant mutants. We propose a simple approach for mutant prediction where the in- put consists of mutation data with drug-resistance information, either as sets of mutations conferring resistance to a certain drug, or as sets of mutants with information on their susceptibility to the drug. The algorithm learns a set of relational rules characterizing drug-resistance, and uses them to generate a set of potentially resistant mutants. Learning a weighted combination of rules allows to attach generated mutants with a resistance score as predicted by the statistical relational model and select only the highest scoring ones. Promising results were obtained in generating resistant mutations for both nucleoside and non-nucleoside HIV reverse transcriptase inhibitors. The ap- proach can be generalized quite easily to learning mutants characterized by more complex rules correlating multiple mutations

HemeBIND: a novel method for heme binding residue prediction by combining structural and sequence information

<p>Abstract</p> <p>Background</p> <p>Accurate prediction of binding residues involved in the interactions between proteins and small ligands is one of the major challenges in structural bioinformatics. Heme is an essential and commonly used ligand that plays critical roles in electron transfer, catalysis, signal transduction and gene expression. Although much effort has been devoted to the development of various generic algorithms for ligand binding site prediction over the last decade, no algorithm has been specifically designed to complement experimental techniques for identification of heme binding residues. Consequently, an urgent need is to develop a computational method for recognizing these important residues.</p> <p>Results</p> <p>Here we introduced an efficient algorithm HemeBIND for predicting heme binding residues by integrating structural and sequence information. We systematically investigated the characteristics of binding interfaces based on a non-redundant dataset of heme-protein complexes. It was found that several sequence and structural attributes such as evolutionary conservation, solvent accessibility, depth and protrusion clearly illustrate the differences between heme binding and non-binding residues. These features can then be separately used or combined to build the structure-based classifiers using support vector machine (SVM). The results showed that the information contained in these features is largely complementary and their combination achieved the best performance. To further improve the performance, an attempt has been made to develop a post-processing procedure to reduce the number of false positives. In addition, we built a sequence-based classifier based on SVM and sequence profile as an alternative when only sequence information can be used. Finally, we employed a voting method to combine the outputs of structure-based and sequence-based classifiers, which demonstrated remarkably better performance than the individual classifier alone.</p> <p>Conclusions</p> <p>HemeBIND is the first specialized algorithm used to predict binding residues in protein structures for heme ligands. Extensive experiments indicated that both the structure-based and sequence-based methods have effectively identified heme binding residues while the complementary relationship between them can result in a significant improvement in prediction performance. The value of our method is highlighted through the development of HemeBIND web server that is freely accessible at <url>http://mleg.cse.sc.edu/hemeBIND/</url>.</p