Structural Alignment - Recent Developments

Recent Developments

Improvements in structural alignment methods constitute an active area of research, and new or modified methods are often proposed that are claimed to offer advantages over the older and more widely distributed techniques. A recent example, TM-align, uses a novel method for weighting its distance matrix, to which standard dynamic programming is then applied. The weighting is proposed to accelerate the convergence of dynamic programming and correct for effects arising from alignment lengths. In a benchmarking study, TM-align has been reported to improve in both speed and accuracy over DALI and CE.

TM-score in TM-align, however, implicitly assumes that two structures align in a length of L (shorter length or average length). In reality, it is quite possible that only a part of a protein of unknown size aligns with a part of another protein, particularly for multidomain proteins. SP-score is proposed to remove the size dependence of alignment score not by size-dependent cutoff but by a size-dependent normalization factor. This allows introduction of an effective alignment length that removes the need to specify a length for normalization. For fold discrimination, SPalign improves sensitivity over TM-align for the chain-level comparison by 12% and over DALI for the domain-level comparison by 13% at the same specificity of 99.6%.

However, as algorithmic improvements and computer performance have erased purely technical deficiencies in older approaches, it has become clear that there is no one universal criterion for the 'optimal' structural alignment. TM-align, for instance, is particularly robust in quantifying comparisons between sets of proteins with great disparities in sequence lengths, but it only indirectly captures hydrogen bonding or secondary structure order conservation which might be better metrics for alignment of evolutionarily related proteins. Thus recent developments have focused on optimizing particular attributes such as speed, quantification of scores, correlation to alternative gold standards, or tolerance of imperfection in structural data or ab initio structural models. An alternative methodology that is gaining popularity is to use the consensus of various methods to ascertain proteins structural similarities.

In choosing among modern algorithms, investigators should strongly consider the optimization for the purpose of intended application, as well as on the algorithm's penetration into the particular field so as to facilitate comparison to other authors' results. For example, MAMMOTH has been specialized for speed and correlation to human annotation, and is thus suited for large-scale structural genomics studies: MAMMOTH has been adopted by Rosetta@home and the World Community Grid's Yeast and Human Proteome Folding projects because it is designed for remote structural homology detection even with relatively inaccurate or incomplete predicted structure models. The venerable DALI is perhaps the most ubiquitous in the literature and due to its integration with other European Bioinformatics Institute web-based tools, the EBI DALI is easily approached by researchers interested in singleton applications.

Historically, it was initially unclear if comparisons that preserved sequence order would be more sensitive than ones that simply compare architecture or contacts without regard to secondary segment ordering. Early versions of DALI allowed a choice of non-sequential alignment at a great cost in speed. Non-sequential methods lost favor as segment order preserving methods outperformed them in speed, quantification of high-confidence similarity scores, and amenability to adoption of rich scoring heuristics. However, in some applications, discovery of conserved but out-of-order structure motif recognition is vital and additionally some forms of experimental data collection, such as cryo-electron microscopy, generally resolve regular secondary elements but not their connection order. This has renewed interest in Non-sequential approaches. Some examples are GANGSTA+ and TOPOFIT.