Now showing 1 - 10 of 25
  • Publication
    Potential utility of docking to identify protein-peptide binding regions
    (University College Dublin. School of Computer Science and Informatics, 2013-05) ; ; ; ;
    Disordered regions of proteins often bind to structured domains, mediating interactions within and between proteins. However, it is difficult to identify a priori the short regions involved in binding. We set out to determine if docking peptides to peptide binding domains would assist in these predictions. First, we investigated the docking of known short peptides to their native and non-native peptide binding domains. We then investigated the docking of overlapping peptides adjacent to the native peptide. We found only weak discrimination of docking scores between native peptide and adjacent peptides in this context with similar results for both ordered and disordered regions. Finally, we trained a bidirectional recurrent neural network using as input the peptide sequence, predicted secondary structure, Vina docking score and Pepsite score.We conclude that docking has only modest power to define the location of a peptide within a larger protein region known to contain it. However, this information can be used in training machine learning methods which may allow for the identification of peptide binding regions within a protein sequence.
  • Publication
    Protein Backbone Angle Prediction in Multidimensional φ-ψ Space
    (University College Dublin. School of Computer Science and Informatics, 2006-01-20) ; ;
    A significant step towards establishing the structure and function of a protein is the prediction of the local conformation of the polypeptide chain. In this article we present systems for the prediction of 3 new alphabets of local structural motifs. The motifs are built by applying multidimensional scaling (MDS) and clustering to pair-wise angular distances for multiple φ-ψ angle values collected from high-resolution protein structures. The predictive systems, based on ensembles of bidirectional recurrent neural network architectures, and trained on a large non-redundant set of protein structures, achieve 72%, 66% and 60% correct structural motif prediction on an independent test set for di-peptides (6 classes), tripeptides (8 classes) and tetra-peptides (14 classes), respectively, 28-30% above base-line statistical predictors. To demonstrate that structural motif predictions contain relevant structural information, we build a further system, based on ensembles of two-layered bidirectional recurrent neural networks, to map structural motif predictions into traditional 3-class (helix, strand, coil) secondary structure. This system achieves 79.5% correct prediction using the “hard” CASP 3-class assignment, and 81.4% with a more lenient assignment, outperforming a sophisticated state-of-the-art predictor (Porter) trained in the same experimental conditions. All the predictive systems will be provided free of charge to academic users and made publicly available at the address
  • Publication
    Pairwise Interaction Field Neural Networks For Drug Discovery
    (University College Dublin. School of Computer Science and Informatics, 2013-06) ;
    Automatically mapping small, drug-like molecules into their biological activity is an open problem in chemioinformatics. Numerous approaches to solve the problem have been attempted, which typically rely on different machine learning tools and, critically, depend on the how a molecule is represented (be it as a one-dimensional string, a two-dimensional graph, its three-dimensional structure, or a feature vector of some kind). In fact arguably the most critical bottleneck in the process is how to encode the molecule in a way that is both informative and can be dealt with by the machine learning algorithms downstream. Recently we have introduced an algorithm which entirely does away with this complex, error-prone and time-consuming encoding step by automatically finding an optimal code for a molecule represented as a twodimensional graph. In this report we introduce a model which we have recently developed (Neural Network Pairwise Interaction Fields) to extend this same approach to molecules represented as their three-dimensional structures. We benchmark the algorithm on a number of public data sets. While our tests confirm that three-dimensional representations are generally less informative than two-dimensional ones (possibly because the former are generally the result of a prediction process, and as such contain noise), the algorithm we introduce compares well with the state of the art in 3D-based prediction, in spite of not requiring any prior knowledge about the domain, or prior encoding of the molecule.
  • Publication
    PeptideLocator: prediction of bioactive peptides in protein sequences
    Motivation: Peptides play important roles in signalling, regulation and immunity within an organism. Many have successfully been used as therapeutic products often mimicking naturally occurring peptides. Here we present PeptideLocator for the automated prediction of functional peptides in a protein sequence. Results: We have trained a machine learning algorithm to predict bioactive peptides within protein sequences. PeptideLocator performs well on training data achieving an area under the curve of 0.92 when tested in 5-fold cross-validation on a set of 2202 redundancy reduced peptide containing protein sequences. It has predictive power when applied to antimicrobial peptides, cytokines, growth factors, peptide hormones, toxins, venoms and other peptides. It can be applied to refine the choice of experimental investigations in functional studies of proteins.
      321Scopus© Citations 65
  • Publication
    Template-based Recognition of Natively Disordered Regions in Proteins
    (University College Dublin. School of Computer Science and Informatics, 2012-04) ; ;
    Disordered proteins are increasingly recognised as a fundamental component of the cellular machinery. Parallel to this, the prediction of protein disorder by computational means has emerged as an aid to the investigation of protein functions. Although predictors of disorder have met with considerable success, it is increasingly clear that further improvements are most likely to come from additional sources of information, to complement patterns extracted from the primary sequence of a protein. In this article, a system for the prediction of protein disorder that relies both on sequence information and on structural information from homologous proteins of known structure (templates) is described. Structural information is introduced directly (as a further input to the predictor) and indirectly through highly reliable template-based predictions of structural features of the protein. The predictive system, based on Support Vector Machines, is tested by rigorous 5-fold cross validation on a large, non-redundant set of proteins extracted from the Protein Data Bank. In these tests the introduction of structural information, which is carefully weighed based on sequence identity between homologues and query, results in large improvements in prediction accuracy. The method, when re-trained on a 2004 version of the PDB, clearly outperforms the algorithms that ranked top at the 2006 CASP competition.
  • Publication
    SCLpred : protein subcellular localization prediction by N-to-1 neural networks
    (Oxford University Press, 2011-08-27) ; ;
    Knowledge of the subcellular location of a protein provides valuable information about its function and possible interaction with other proteins. In the post-genomic era, fast and accurate predictors of subcellular location are required if this abundance of sequence data is to be fully exploited. We have developed a subcellular localization predictor (SCLpred), which predicts the location of a protein into four classes for animals and fungi and five classes for plants (secreted, cytoplasm, nucleus, mitochondrion and chloroplast) using machine learning models trained on large non-redundant sets of protein sequences. The algorithm powering SCLpred is a novel Neural Network (N-to-1 Neural Network, or N1-NN) we have developed, which is capable of mapping whole sequences into single properties (a functional class, in this work) without resorting to predefined transformations, but rather by adaptively compressing the sequence into a hidden feature vector. We benchmark SCLpred against other publicly available predictors using two benchmarks including a new subset of Swiss-Prot Release 2010_06. We show that SCLpred surpasses the state of the art. The N1-NN algorithm is fully general and may be applied to a host of problems of similar shape, that is, in which a whole sequence needs to be mapped into a fixed-size array of properties, and the adaptive compression it operates may shed light on the space of protein sequences. The predictive systems described in this article are publicly available as a web server at
    Scopus© Citations 52  415
  • Publication
    Protein Structure Annotations
    (Springer, 2019-03-28) ;
    This chapter aims to introduce to the specifics of protein structure annotations and their fundamental position in structural bioinformatics, bioinformatics in general. Proteins are profoundly characterised by their structure in every aspect of their functioning and, while over the last decades there has been a close to exponential growth of known protein sequences, the growth of known protein structures has been closer to linear because of the high complexity and cost of determining them. Thus, protein structure predictors are among the most thoroughly assessed tools in bioinformatics (in venues such as CASP or CAMEO) because they allow the structural study of proteins on a large scale. This chapter presents the key types of protein structure annotation and the methods and algorithms for predicting them, with the aim to give both a historical perspective on their development and a snapshot of their current state of the art. From one-dimensional protein annotations – i.e. secondary structure, solvent accessibility and torsion angles – to more complex and informative two-dimensional protein abstractions, i.e. contact maps, both mature and currently developing methods for protein structure annotations are introduced. The aim of this overview is to facilitate the adoption and development of state-of-the-art protein structural predictors. Particular attention is given to some of the best performing and freely available web servers and standalone programmes to predict protein structure annotations.
      354Scopus© Citations 6
  • Publication
    PaleAle 5.0: prediction of protein relative solvent accessibility by deep learning
    Predicting the three-dimensional structure of proteins is a long-standing challenge of computational biology, as the structure (or lack of a rigid structure) is well known to determine a protein's function. Predicting relative solvent accessibility (RSA) of amino acids within a protein is a significant step towards resolving the protein structure prediction challenge especially in cases in which structural information about a protein is not available by homology transfer. Today, arguably the core of the most powerful prediction methods for predicting RSA and other structural features of proteins is some form of deep learning, and all the state-of-the-art protein structure prediction tools rely on some machine learning algorithm. In this article we present a deep neural network architecture composed of stacks of bidirectional recurrent neural networks and convolutional layers which is capable of mining information from long-range interactions within a protein sequence and apply it to the prediction of protein RSA using a novel encoding method that we shall call "clipped". The final system we present, PaleAle 5.0, which is available as a public server, predicts RSA into two, three and four classes at an accuracy exceeding 80% in two classes, surpassing the performances of all the other predictors we have benchmarked.
      383Scopus© Citations 22
  • Publication
    SCL-Epred: A generalised de novo eukaryotic protein subcellular localisation predictor
    Knowledge of the subcellular location of a protein provides valuable information about its function, possible interaction with other proteins and drug targetability, among other things. The experimental determination of a protein's location in the cell is expensive, time consuming and open to human error. Fast and accurate predictors of subcellular location have an important role to play if the abundance of sequence data which is now available is to be fully exploited. In the post-genomic era, genomes in many diverse organisms are available. Many of these organisms are important in human and veterinary disease and fall outside of the well-studied plant, animal and fungi groups. We have developed a general eukaryotic subcellular localisation predictor (SCL-Epred) which predicts the location of eukaryotic proteins into three classes which are important, in particular, for determining the drug targetability of a protein - secreted proteins, membrane proteins and proteins that are neither secreted nor membrane. The algorithm powering SCL-Epred is a N-to-1 neural network and is trained on very large non-redundant sets of protein sequences. SCL-Epred performs well on training data achieving a Q of 86 % and a generalised correlation of 0.75 when tested in tenfold cross-validation on a set of 15,202 redundancy reduced protein sequences. The three class accuracy of SCL-Epred and LocTree2, and in particular a consensus predictor comprising both methods, surpasses that of other widely used predictors when benchmarked using a large redundancy reduced independent test set of 562 proteins. SCL-Epred is publicly available at
      212Scopus© Citations 8
  • Publication
    Distill : a suite of web servers for the prediction of one-, two- and three-dimensional structural features of proteins
    We describe Distill, a suite of servers for the prediction of protein structural features: secondary structure; relative solvent accessibility; contact density; backbone structural motifs; residue contact maps at 6, 8 and 12 Angstrom; coarse protein topology. The servers are based on large-scale ensembles of recursive neural networks and trained on large, up-to-date, non- redundant subsets of the Protein Data Bank. Together with structural feature predictions, Distill includes a server for prediction of Cα traces for short proteins (up to 200 amino acids). The servers are state-of-the-art, with secondary structure predicted correctly for nearly 80% of residues (currently the top performance on EVA), 2-class solvent accessibility nearly 80% correct, and contact maps exceeding 50% precision on the top non-diagonal contacts. A preliminary implementation of the predictor of protein Cα traces featured among the top 20 Novel Fold predictors at the last CASP6 experiment as group Distill (ID 0348). The majority of the servers, including the Cα trace predictor, now take into account homology information from the PDB, when available, resulting in greatly improved reliability. All predictions are freely available through a simple joint web interface and the results are returned by email. In a single submission the user can send protein sequences for a total of up to 32k residues to all or a selection of the servers. Distill is accessible at the address:
    Scopus© Citations 84  565