DominoEffect

DominoEffect identifies and annotates hotspot amino acid residues in proteins to detect positions with elevated mutation rates that may indicate functional impact and drive cancer.

Key Features:

• Hotspot Identification: Pinpoints individual amino acids that accumulate mutations at significantly higher frequency than surrounding residues and highlights specific nucleotide positions prone to change.
• Functional Annotation: Provides detailed annotations of hotspot residues indicating potential roles in protein function and interactions.
• Cancer Driver Prioritization: Aids distinction of driver genes in cancer genome sequencing by highlighting recurrently mutated residues and nucleotide positions.
• Structural Interface Analysis: Extends analysis to structural data from human protein complexes to identify protein–protein and protein–ligand interfaces enriched for mutations.
• State-Dependent Mutation Detection: Detects enrichment of hotspot mutations in proteins capable of existing in both active and inactive states.
• Tumor-Origin Correlation: Identifies correlations between tumor identity and mutation patterns at hotspot residues.

Scientific Applications:

• Driver gene discovery in cancer genomics: Prioritizes candidate driver genes and specific hotspot residues from cancer genome sequencing data.
• Mechanistic interpretation of tumorigenesis: Links hotspot residues to disruption of protein function or interactions to inform molecular mechanisms of cancer.
• Structural mapping of mutations: Maps recurrent mutations onto human protein complex structures and interfaces to reveal interaction-disrupting hotspots.
• Target prioritization for therapeutic intervention: Highlights specific mutated residues and interfaces as potential targets for therapeutic development.

Methodology:

Using a novel methodological framework, DominoEffect systematically investigates properties associated with residues' potential to drive cancer when mutated and extends its analysis to structural data from human protein complexes.