Dependency

Dependency detects functional interactions between amino acids in proteins by identifying co-variations in multiple sequence alignments of homologous proteins that reflect compensatory substitutions under functional constraints.

Key Features:

• Multiple Sequence Alignments: Uses multiple sequence alignments of homologous proteins as the primary dataset to identify sites under functional constraint.
• Detection of Co-Variation: Identifies co-variations where substitutions at one amino-acid site are accompanied by compensatory changes at another site.
• Statistical Correlation Analysis: Applies statistical correlation analysis to separate signals of functional co-variation from correlations caused by phylogenetic clustering or other confounders.
• Independence from Phylogeny Assumptions: Operates without requiring assumptions about the underlying phylogeny or substitution processes.
• Verification and Application: Was validated by computer simulations and applied to predict functional interactions in Pfam alignments.

Scientific Applications:

• Protein functional inference: Infers functionally coupled residues to inform structural and functional interpretation of proteins.
• Evolutionary analysis: Analyzes evolutionary constraints and compensatory substitutions across homologous sequences.
• Mutation effect prediction: Aids prediction of mutational effects by identifying compensatory sites that modulate functional impact.
• Disease mechanism investigation: Supports investigation of disease mechanisms by highlighting amino-acid interactions whose disruption may impair protein function.
• Protein engineering and design: Informs protein design by identifying residue pairs that co-evolve and may be targeted to preserve or alter function.

Methodology:

Analyzes multiple sequence alignments of homologous proteins to detect amino-acid co-variations via statistical correlation analysis, explicitly filters phylogenetic signals without assuming a specific phylogeny or substitution model, and was validated by computer simulations and applied to Pfam alignments.