ASH structure alignment package: Sensitivity and selectivity in domain classification

The new ASH score shows increased selectivity and sensitivity compared with values reported for several popular programs using the same test set of 4,298,905 structure pairs, yielding an area of .96 under the receiver operating characteristic (ROC) curve. In addition, weak sequence homologies between similar domains are revealed that could not be detected by BLAST sequence alignment. Also, a subset of domain pairs is identified that exhibit high similarity, even though their CATH and SCOP classification differs. Finally, we show that the ranking of alignment programs based solely on geometric measures depends on the choice of the quality measure.ASH shows high selectivity and sensitivity with regard to domain classification, an important step in defining distantly related protein sequence families. Moreover, the CPU cost per alignment is competitive with the fastest programs, making ASH a practical option for large-scale structure classification studies.The last decade has witnessed enormous growth in our knowledge of gene sequences. Efforts are now being made to put this knowledge into a structural context by determining the structures of proteins associated with all known gene families. Protein structure alignment methods are essential for interpreting such data, as they provide a means for detecting evolutionary and functional relationships between distantly related proteins[1]. In practice, however, the problem of quantifying evolutionary distance beyond what is observable through sequence analysis is far from simple. In particular, it is not clear what measure should be used to compare structural domains, and what threshold should be used to judge if they are likely to be related.These questions were investigated in two recent studies by Sierk and Pearson[2] and by Kolody, et al.[3], where a number of structure alignment methods were tested in terms of their ability to correctly identify domains with the same CATH[4] topology. The sensitivity and selectivity of