INTREPID

INTREPID predicts functionally important residues in proteins, including catalytic residues, by scoring residue positions using multiple sequence alignments and phylogenetic trees to detect conserved and spatially conserved sites.

Key Features:

• Functional residue prediction: Predicts functionally important residues, including catalytic residues and other functional sites.
• Homologous sequence retrieval: Gathers homologous sequences to inform conservation analysis.
• Multiple sequence alignment: Constructs a multiple sequence alignment from retrieved homologs.
• Phylogenetic analysis: Builds a phylogenetic tree to represent evolutionary relationships among homologs.
• Residue scoring: Assigns scores to each residue position based on the multiple sequence alignment and phylogenetic tree.
• Spatial conservation assessment: Leverages patterns of spatial conservation at various significance thresholds to highlight likely functional sites.
• Structural mapping: Maps and visually represents predicted residues on homologous 3D structures when available.
• Performance focus: Aims to improve recall and precision relative to existing sequence-based methods.

Scientific Applications:

• Catalytic residue identification: Identification of catalytic residues in enzymes through conserved and spatially conserved residues.
• Functional site annotation: Annotation of other protein functional sites and critical amino acid positions.
• Structural biology: Interpretation of conserved residues in the context of homologous 3D structures.
• Enzymology: Informing studies of enzyme mechanism and active-site composition.
• Evolutionary studies: Investigating evolutionary conservation and functional divergence across homologs.

Methodology:

Upon receiving an input protein sequence, INTREPID gathers homologous sequences, constructs a multiple sequence alignment and a phylogenetic tree, assigns scores to residue positions based on those alignments and the tree, assesses spatial conservation, and maps predictions onto homologous 3D structures.