A local comparison across conformations
The method follows loop-like features in the protein’s Cα geometry and compares their persistence across static or generated conformations. Candidate regions are checked against background and null controls. A strong local difference suggests where to inspect the structure; it does not measure the fraction of time a pocket is open.
Topology already has a place in pocket discovery
CrypToth combines persistent homology with mixed-solvent molecular dynamics. BioTwin’s specific route uses local Cα comparisons and can feed candidate regions into its all-atom fit/access and ensemble-ligandability methods. This creates a staged investigation: locate an opening, test whether a molecule can enter, then examine whether useful chemistry is available there. The combined biological benefit remains a target-specific question.
The controls changed the interpretation
Selected known-site and two-structure studies localized useful regions. A broader apo-only panel did not establish a general discovery advantage, and a structural null explained much of one apparent mutation-specific signal. Those findings make matched structures and negative controls essential. Side-chain pockets may also be missed by a Cα representation.