Using evolutionary information for the query and target improves fold recognition

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Abstract
In this study, we show that it is possible to increase the performance over PSI‐BLAST by using evolutionary information for both query and target sequences. This information can be used in three different ways: by sequence linking, profile–profile alignments, and by combining sequence–profile and profile–sequence searches. If only PSI‐BLAST is used, 16% of superfamily‐related protein domains can be detected at 90% specificity, but if a sequence–profile and a profile–sequence search are combined, this is increased to 20%, profile–profile searches detects 19%, whereas a linking procedure identifies 22% of these proteins. All three methods show equal performance, but the best combination of speed and accuracy seems to be obtained by the combined searches, because this method shows a good performance even at high specificity and the lowest computational cost. In addition, we show that the E‐values reported by all these methods, including PSI‐BLAST, underestimate the true rate of false positives. This behavior is seen even if a very strict E‐value cutoff and a limited number of iterations are used. However, the difference is more pronounced with a looser E‐value cutoff and more iterations. Proteins 2003;53:000–000.