Direct Detection and Atomic Modeling of Ligands in Cryo-EM Maps Using Deep Learning

Abstract

Cryogenic electron microscopy (cryo-EM) has become an increasingly important for structure-based drug discovery by enabling characterization of interactions between macromolecules and small-molecule ligands. However, computational interpretation of ligand density remains challenging, particularly when ligand locations are unknown or local map resolution is limited. Existing methods generally require well-resolved macromolecular structures and predefined binding sites, limiting their applicability during early-stage structure determination. To date, no approach has been able to both reliably detect ligand density and subsequently reconstruct ligand atomic structures directly from experimental cryo-EM maps. Here, we present Emap2lig, a two-stage deep learning framework for automated ligand detection and atomic modeling directly from cryo-EM maps. Emap2lig-Find identifies ligand-associated densities and remains effective for maps at resolutions as low as [~]5 [A]. Emap2lig-Build subsequently uses a diffusion-based generative model to build atomic ligand structures. Together, Emap2lig provides a unified framework for ligand discovery and modeling across a broad range of resolutions.