PSI-Search (EBI)

PSI-Search performs iterative protein sequence similarity searches by combining Smith-Waterman local alignments with PSI-BLAST PSSM construction to detect distant homologous protein sequences.

Key Features:

• Optimal Alignment Strategy: Uses SSEARCH (Smith-Waterman) for optimal local alignments to identify precise local similarities.
• Profile Construction with PSSMs: Constructs Position-Specific Score Matrices (PSSMs) via a PSI-BLAST iterative profile construction strategy to enhance homolog detection.
• Homologous Over-Extension Mitigation: Implements an optional sequence boundary-masking procedure to prevent alignments extending into unrelated domains and reduce homologous over-extension (HOE).
• Improved Selectivity and Sensitivity: Reports approximately four-fold better selectivity than PSI-BLAST with similar sensitivity at 50% and 60% family coverage, and produces fewer false positives than JackHMMER while being slightly (~5%) less sensitive.

Scientific Applications:

• Homology detection: Identification of distant homologous protein sequences using iterative PSSM-based searches and optimal local alignments.
• Evolutionary biology: Analysis of protein family membership and distant evolutionary relationships informed by selective PSSM profiles.
• Functional genomics and proteomics: Improved assignment of protein function and family annotation by reducing false positives in similarity searches.

Methodology:

Combines SSEARCH (Smith-Waterman) local alignment searches with iterative PSI-BLAST PSSM construction and an optional sequence boundary-masking step to mitigate homologous over-extension.