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Published on: October 24, 2025
Pathway representation via intrinsic structural medoids (PRISM): a structural mapping approach to clustering
Jherome Brylle Woody Santos1, Jeremy M G Leung2, Lillian T Chong2
1Department of Chemistry and Quantum Theory Project, University of Florida Gainesville Florida 32611 USA quintana@chem.ufl.edu.
Abstract:
We present Pathway Representation via Intrinsic Structural Medoids (PRISM), a state-aware framework for clustering pathways from molecular dynamics simulations of biomolecular transitions. In PRISM, each pathway is mapped to a small set of structural medoids obtained via a deterministic k-means clustering scheme. Pairwise pathway dissimilarities are computed using a weighted average Hausdorff distance between these representative sets, effectively capturing mean nearest-neighbor structural deviations while reducing sensitivity to outliers. Hierarchical agglomerative clustering of the resulting dissimilarity matrix defines pathway families. We evaluate PRISM across three biomolecular transitions of increasing complexity: alanine dipeptide C7eq → C7ax isomerization, adenylate kinase opening, and HIF-2α PAS-B ligand unbinding. PRISM consistently yields robust cluster assignments, with medoids faithfully representing distinct conformational states. By combining a state-based description with robust geometric dissimilarities, PRISM provides a scalable framework for organizing complex transition pathways.
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