DiffModeler: large macromolecular structure modeling for cryo-EM maps using a diffusion model

Abstract

Cryogenic electron microscopy (cryo-EM) has now been widely used for determining multichain protein complexes. However, modeling a large complex structure, such as those with more than ten chains, is challenging, particularly when the map resolution decreases. Here we present DiffModeler, a fully automated method for modeling large protein complex structures. DiffModeler employs a diffusion model for backbone tracing and integrates AlphaFold2-predicted single-chain structures for structure fitting. DiffModeler showed an average template modeling score of 0.88 and 0.91 for two datasets of cryo-EM maps of 0–5 Å resolution and 0.92 for intermediate resolution maps (5–10 Å), substantially outperforming existing methodologies. Further benchmarking at low resolutions (10–20 Å) confirms its versatility, demonstrating plausible performance. DiffModeler is a fully automated structure fitting method for modeling large protein complex structures in cryo-EM maps with resolutions up to 15 Å.