A physically interpretable symbolic language of molecular recognition
Abstract
Despite decades of structural biology and molecular modelling, molecular recognition remains predominantly interpreted through static structural representations, although it is inherently dynamic. Here we represent protein-ligand recognition as a language-like statistical process arising from sequential interaction dependencies over time, through STRIPES (Spatio-Temporal Representation of Interactions in Protein-ligand Engagement Strings), a conceptual framework that encodes molecular interaction dynamics as symbolic sequences. By discarding explicit coordinates while preserving interaction semantics, STRIPES captures recognition-relevant temporal information inaccessible to conventional structural representations. Across 14,000 molecular dynamics trajectories, 2,000 distinct proteins, and 7,000 chemotypes in the Protein Data Bank, STRIPES reveals structured sequential dependencies and conserved interaction motifs that transcend protein families and molecular motifs, compressing high-dimensional trajectories into compact symbolic sequences while enabling interaction-driven similarity analysis and generative molecular design. Leveraging sequence-to-sequence deep learning, interaction patterns can be translated into chemically valid and bioactive ligands, including compounds with experimentally reported picomolar and nanomolar potency. By recasting molecular recognition as an emergent symbolic process, STRIPES establishes a generalizable conceptual framework for comparing, learning, and engineering biomolecular interactions beyond static structural information.