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Motivation Protein pocket information is invaluable for drug target identification, agonist design, virtual screening and receptor-ligand binding analysis. A recent study indicates that about half holoproteins can simultaneously bind multiple interacting ligands in a large pocket containing structured sub-pockets. Although this hierarchical pocket and sub-pocket structure has a significant impact to multi-ligand synergistic interactions in the protein binding site, there is no method available for this analysis. This work introduces a computational tool based on differential geometry, algebraic topology and physics-based simulation to address this pressing issue. Results We propose to detect protein pockets by evolving the convex hull surface inwards until it touches the protein surface everywhere. The governing partial differential equations (PDEs) include the mean curvature flow combined with the eikonal equation commonly used in the fast marching algorithm in the Eulerian representation. The surface evolution induced Morse function and Reeb graph are utilized to characterize the hierarchical pocket and sub-pocket structure in controllable detail. The proposed method is validated on PDBbind refined sets of 4414 protein-ligand complexes. Extensive numerical tests indicate that the proposed method not only provides a unique description of pocket-sub-pocket relations, but also offers efficient estimations of pocket surface area, pocket volume and pocket depth. Availability and implementation Source code available at https://github.com/rdzhao/ProteinPocketDetection. Webserver available at http://weilab.math.msu.edu/PPD/. [ABSTRACT FROM AUTHOR]