ATTRACT-EM: a new method for the computational assembly of large molecular machines using cryo-EM maps

Many of the most important functions in the cell are carried out by proteins organized in large molecular machines. Cryo-electron microscopy (cryo-EM) is increasingly being used to obtain low resolution density maps of these large assemblies. A new method, ATTRACT-EM, for the computational assembly of molecular assemblies from their components has been developed. Based on concepts from the protein-protein docking field, it utilizes cryo-EM density maps to assemble molecular subunits at near atomic detail, starting from millions of initial subunit configurations. The search efficiency was further enhanced by recombining partial solutions, the inclusion of symmetry information, and refinement using a molecular force field. The approach was tested on the GroES-GroEL system, using an experimental cryo-EM map at 23.5 Å resolution, and on several smaller complexes. Inclusion of experimental information on the symmetry of the systems and the application of a new gradient vector matching algorithm allowed the efficient identification of docked assemblies in close agreement with experiment. Application to the GroES-GroEL complex resulted in a top ranked model with a deviation of 4.6 Å (and a 2.8 Å model within the top 10) from the GroES-GroEL crystal structure, a significant improvement over existing methods.