ProBiS-Fold

ProBiS-Fold annotates AlphaFold-predicted protein structures with putative small-molecule binding sites by comparing them to PDB structures and transferring ligand information to support druggability assessment.

Key Features:

• Structure-Based Comparison: Uses the ProBiS algorithm to compare each AlphaFold-predicted protein structure against PDB structures to identify similar known binding sites.
• Ligand Transfer and Binding Site Identification: Transfers ligands bound in matching PDB binding sites onto corresponding AlphaFold models and identifies small-molecule binding sites as clusters on the AlphaFold structures.
• Druggability Scoring: Assigns druggability scores to identified binding sites based on ligand similarity to known drugs to prioritize sites for drug development.
• Proteome Coverage and Novel Site Discovery: Covers the entire human structural proteome and identifies over 3,000 new druggable binding sites lacking corresponding PDB structures.
• Quality Consideration: Incorporates AlphaFold model quality assessments to inform confidence in binding-site annotations.

Scientific Applications:

• Novel Target Identification: Annotates AlphaFold structures lacking PDB counterparts to reveal novel druggable targets within the human proteome.
• Prioritization for Validation and Drug Development: Ranks and prioritizes predicted binding sites for experimental validation and small-molecule therapeutic development using druggability scores.

Methodology:

Systematic comparison of AlphaFold-predicted structures against PDB structures using the ProBiS algorithm to identify structural similarities, transfer ligand information from matching PDB binding sites to AlphaFold models, define binding-site clusters from transferred ligands, and assign druggability scores to refine predictions, with AlphaFold model quality assessments informing annotation confidence.