Measuring the similarity of protein structures by means of the universal similarity metric

Motivation: As an increasing number of protein structures become available, the need for algorithms that can quantify the similarity between protein structures increases as well. Thus, the comparison of proteins’ structures, and their clustering accordingly to a given similarity measure, is at the core of today’s biomedical research. In this paper, we show how an algorithmic information theory inspired Universal Similarity Metric (USM) can be used to calculate similarities between protein pairs.The method, besides being theoretically supported, is surprisingly simple to implement and computationally efficient. Results: Structural similarity between proteins in four different datasets was measured using the USM.The sample employed represented alpha, beta, alpha–beta, tim–barrel, globins and serpine protein types. The use of the proposed metric allows for a correct measurement of similarity and classification of the proteins in the four datasets. Availability: All the scripts and programs used for the preparation of this paper are available at http://www.cs.nott.ac.uk/ ~nxk/USM/protocol.html. In that web-page the reader will find a brief description on how to use the various scripts and programs.TIC2002-04242-C03-0

Identification of functionally related enzymes by learning-to-rank methods

Enzyme sequences and structures are routinely used in the biological sciences as queries to search for functionally related enzymes in online databases. To this end, one usually departs from some notion of similarity, comparing two enzymes by looking for correspondences in their sequences, structures or surfaces. For a given query, the search operation results in a ranking of the enzymes in the database, from very similar to dissimilar enzymes, while information about the biological function of annotated database enzymes is ignored. In this work we show that rankings of that kind can be substantially improved by applying kernel-based learning algorithms. This approach enables the detection of statistical dependencies between similarities of the active cleft and the biological function of annotated enzymes. This is in contrast to search-based approaches, which do not take annotated training data into account. Similarity measures based on the active cleft are known to outperform sequence-based or structure-based measures under certain conditions. We consider the Enzyme Commission (EC) classification hierarchy for obtaining annotated enzymes during the training phase. The results of a set of sizeable experiments indicate a consistent and significant improvement for a set of similarity measures that exploit information about small cavities in the surface of enzymes

Towards a Theory of Scale-Free Graphs: Definition, Properties, and Implications (Extended Version)

Although the ``scale-free'' literature is large and growing, it gives neither a precise definition of scale-free graphs nor rigorous proofs of many of their claimed properties. In fact, it is easily shown that the existing theory has many inherent contradictions and verifiably false claims. In this paper, we propose a new, mathematically precise, and structural definition of the extent to which a graph is scale-free, and prove a series of results that recover many of the claimed properties while suggesting the potential for a rich and interesting theory. With this definition, scale-free (or its opposite, scale-rich) is closely related to other structural graph properties such as various notions of self-similarity (or respectively, self-dissimilarity). Scale-free graphs are also shown to be the likely outcome of random construction processes, consistent with the heuristic definitions implicit in existing random graph approaches. Our approach clarifies much of the confusion surrounding the sensational qualitative claims in the scale-free literature, and offers rigorous and quantitative alternatives.Comment: 44 pages, 16 figures. The primary version is to appear in Internet Mathematics (2005

An optimized TOPS+ comparison method for enhanced TOPS models

This article has been made available through the Brunel Open Access Publishing Fund.Background Although methods based on highly abstract descriptions of protein structures, such as VAST and TOPS, can perform very fast protein structure comparison, the results can lack a high degree of biological significance. Previously we have discussed the basic mechanisms of our novel method for structure comparison based on our TOPS+ model (Topological descriptions of Protein Structures Enhanced with Ligand Information). In this paper we show how these results can be significantly improved using parameter optimization, and we call the resulting optimised TOPS+ method as advanced TOPS+ comparison method i.e. advTOPS+. Results We have developed a TOPS+ string model as an improvement to the TOPS [1-3] graph model by considering loops as secondary structure elements (SSEs) in addition to helices and strands, representing ligands as first class objects, and describing interactions between SSEs, and SSEs and ligands, by incoming and outgoing arcs, annotating SSEs with the interaction direction and type. Benchmarking results of an all-against-all pairwise comparison using a large dataset of 2,620 non-redundant structures from the PDB40 dataset [4] demonstrate the biological significance, in terms of SCOP classification at the superfamily level, of our TOPS+ comparison method. Conclusions Our advanced TOPS+ comparison shows better performance on the PDB40 dataset [4] compared to our basic TOPS+ method, giving 90 percent accuracy for SCOP alpha+beta; a 6 percent increase in accuracy compared to the TOPS and basic TOPS+ methods. It also outperforms the TOPS, basic TOPS+ and SSAP comparison methods on the Chew-Kedem dataset [5], achieving 98 percent accuracy. Software Availability: The TOPS+ comparison server is available at http://balabio.dcs.gla.ac.uk/mallika/WebTOPS/.This article is available through the Brunel Open Access Publishing Fun