An optimized TOPS+ comparison method for enhanced TOPS models

Abstract

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 123 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% accuracy for SCOP alpha+beta; a 6% 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% accuracy.

Software availability: The TOPS+ comparison server is available at http://balabio.dcs.gla.ac.uk/mallika/WebTOPS/.

Figure 1

ROC curves for the PDB40 dataset. ROC curves for SCOP classes all-alpha, all-beta, alpha/beta and alpha+beta from TOPS, TOPS+ and advanced TOPS+ methods on the PDB40 dataset.

Figure 2

Clusters for the Chew-Kedem dataset. Chew-Kedem dataset clusters obtained from the advanced TOPS+ comparison method (for more information see the supplementary material page at http://balabio.dcs.gla.ac.uk/mallika/WebTOPS/optTOPSplus-results.html).

Figure 3

Protein domain 3D cartoon diagrams. 3D cartoon diagrams (top view) of the alpha-beta protein domains (a) d1aa9__, (b) d1ct9a1, (c) TIM barrel protein domain d6xia__. Beta-strands, alpha-helices and loops are colored with yellow, red and green, respectively. Ligand molecules are indicated by spheres and dots (metals).

Figure 4

TOPS+ representation of a protein domain. TOPS+ diagram and string representation of the protein domain 1fnb01. (a) TOPS+ diagram. (b) TOPS+ string. (c) 3D cartoon.

Figure 5

Parameter optimization results for SCOP classes. Parameter optimization experimental results for SCOP classes all-alpha, all-beta, alpha/beta, alpha+beta, and all classes together. Each element in the matrix represents the AUC values based on the 17 nC scores corresponding to the basic parameters. The x-axis represents 1,134 basic parameters and the y-axis represents the 17 nC scores from 1 through 17 represented in a block which is repeated five times along the y-axis and each block corresponding to the SCOP classes all-alpha, all-beta, alpha/beta, alpha+beta, and all classes together.