Quantitative method for the assignment of hinge and shear mechanism in protein domain movements

Motivation: A popular method for classification of protein domain movements apportions them into two main types: those with a ‘hinge’ mechanism and those with a ‘shear’ mechanism. The intuitive assignment of domain movements to these classes has limited the number of domain movements that can be classified in this way. Furthermore, whether intended or not, the term ‘shear’ is often interpreted to mean a relative translation of the domains. Results: Numbers of occurrences of four different types of residue contact changes between domains were optimally combined by logistic regression using the training set of domain movements intuitively classified as hinge and shear to produce a predictor for hinge and shear. This predictor was applied to give a 10-fold increase in the number of examples over the number previously available with a high degree of precision. It is shown that overall a relative translation of domains is rare, and that there is no difference between hinge and shear mechanisms in this respect. However, the shear set contains significantly more examples of domains having a relative twisting movement than the hinge set. The angle of rotation is also shown to be a good discriminator between the two mechanisms. Availability and implementation: Results are free to browse at http:// www.cmp.uea.ac.uk/dyndom/interface/. Supplementary information: Supplementary data are available at Bioinformatics online

Investigation of sequence features of hinge-bending regions in proteins with domain movements using kernel logistic regression

Background: Hinge-bending movements in proteins comprising two or more domains form a large class of functional movements. Hinge-bending regions demarcate protein domains and collectively control the domain movement. Consequently, the ability to recognise sequence features of hinge-bending regions and to be able to predict them from sequence alone would benefit various areas of protein research. For example, an understanding of how the sequence features of these regions relate to dynamic properties in multi-domain proteins would aid in the rational design of linkers in therapeutic fusion proteins. Results: The DynDom database of protein domain movements comprises sequences annotated to indicate whether the amino acid residue is located within a hinge-bending region or within an intradomain region. Using statistical methods and Kernel Logistic Regression (KLR) models, this data was used to determine sequence features that favour or disfavour hinge-bending regions. This is a difficult classification problem as the number of negative cases (intradomain residues) is much larger than the number of positive cases (hinge residues). The statistical methods and the KLR models both show that cysteine has the lowest propensity for hinge-bending regions and proline has the highest, even though it is the most rigid amino acid. As hinge-bending regions have been previously shown to occur frequently at the terminal regions of the secondary structures, the propensity for proline at these regions is likely due to its tendency to break secondary structures. The KLR models also indicate that isoleucine may act as a domain-capping residue. We have found that a quadratic KLR model outperforms a linear KLR model and that improvement in performance occurs up to very long window lengths (eighty residues) indicating long-range correlations. Conclusion: In contrast to the only other approach that focused solely on interdomain hinge-bending regions, the method provides a modest and statistically significant improvement over a random classifier. An explanation of the KLR results is that in the prediction of hinge-bending regions a long-range correlation is at play between a small number amino acids that either favour or disfavour hinge-bending regions. The resulting sequence-based prediction tool, HingeSeek, is available to run through a webserver at hingeseek.cmp.uea.ac.uk

Novel methods for multi-view learning with applications in cyber security

Modern data is complex. It exists in many different forms, shapes and kinds. Vectors, graphs, histograms, sets, intervals, etc.: they each have distinct and varied structural properties. Tailoring models to the characteristics of various feature representations has been the subject of considerable research. In this thesis, we address the challenge of learning from data that is described by multiple heterogeneous feature representations. This situation arises often in cyber security contexts. Data from a computer network can be represented by a graph of user authentications, a time series of network traffic, a tree of process events, etc. Each representation provides a complementary view of the holistic state of the network, and so data of this type is referred to as multi-view data. Our motivating problem in cyber security is anomaly detection: identifying unusual observations in a joint feature space, which may not appear anomalous marginally. Our contributions include the development of novel supervised and unsupervised methods, which are applicable not only to cyber security but to multi-view data in general. We extend the generalised linear model to operate in a vector-valued reproducing kernel Hilbert space implied by an operator-valued kernel function, which can be tailored to the structural characteristics of multiple views of data. This is a highly flexible algorithm, able to predict a wide variety of response types. A distinguishing feature is the ability to simultaneously identify outlier observations with respect to the fitted model. Our proposed unsupervised learning model extends multidimensional scaling to directly map multi-view data into a shared latent space. This vector embedding captures both commonalities and disparities that exist between multiple views of the data. Throughout the thesis, we demonstrate our models using real-world cyber security datasets.Open Acces

Classification of Protein Domain Movements using Dynamic Contact Graphs

Protein domain movements are of critical importance for understanding macromolecular function, but little is understood about how they are controlled, their energetics, and how to characterize them into meaningful descriptions for the purpose of understanding their relation to function. Here we have developed new methods for this purpose based on changes in residue contacts between domains. The main tool used is the “Dynamic Contact Graph” which in one static graph depicts changes in contacts between residues from the domains. The power of this method is twofold: first the graphs allow one to use the algorithms of graph theory in the analysis of domain movements, and second they provide a visual metaphor for the movements they depict. Using this method it was possible to classify 1822 domain movements from the “Non-Redundant Database of Protein Domain Movements” into sixteen different classes by decomposing the graphs for each individual protein into four elemental graphs which represent the four types of elemental contact change. For each individual domain movement the output of this process provides the numbers of occurrences of each type of elemental contact change. These were used as input for logistic regression to create a predictor of hinge and shear using assignments for these two mechanisms at the "Database of Macromolecular Movements". This predictor was applied to the 1822 domain movements to give a tenfold increase in the number of examples classified as hinge and shear. Using this dataset it was shown that contrary to common interpretation there is no difference between hinge and shear domain movements. The new data is presented online with new websites which give visual depictions of the protein domain movements

Generalised Kernel Machines

Abstract — The generalised linear model (GLM) is the standard approach in classical statistics for regression tasks where it is appropriate to measure the data misfit using a likelihood drawn from the exponential family of distributions. In this paper, we apply the kernel trick to give a non-linear variant of the GLM, the generalised kernel machine (GKM), in which a regularised GLM is constructed in a fixed feature space implicitly defined by a Mercer kernel. The MATLAB symbolic maths toolbox is used to automatically create a suite of generalised kernel machines, including methods for automated model selection based on approximate leave-one-out cross-validation. In doing so, we provide a common framework encompassing a wide range of existing and novel kernel learning methods, and highlight their connections with earlier techniques from classical statistics. Examples including kernel ridge regression