Computational approaches for protein complex modeling for intermediate resolution cryo-EM maps

Cryogenic electron microscopy (cryo-EM) has become a central technology for determining macromolecular structures in structural biology. However, interpreting density maps by structure modeling from intermediate (∼5-10Å) to low resolution (over 10Å) cryo-EM maps often remains challenging. To meet the demand for accurate modeling tools in cryo-EM, we developed the EMSuite server (https://em.kiharalab.org/), a freely accessible platform that provides 14 computational tools for structure modeling and validation. In this chapter, we focus on three methods developed for intermediate resolution maps, DiffModeler, DMcloud, and VESPER, presenting their usages through the web server. DiffModeler builds full protein complexes by enhancing backbone positions with a diffusion-based generative model and using AlphaFold to predict structural models. Similarly, DMcloud performs local structure fitting instead of global structure fitting to eliminate incompatible regions in structure models to the map. Finally, VESPER is a general-use structure fitting method, which performs global structure-map and map-map fitting.