Cryo-electron microscopy (cryoEM) can visualize large macromolecular assemblies at resolutions often below 10Å and recently as good as 3.8-4.5 Å. These density maps provide important insights into the biological functioning of molecular machineries such as viruses or the ribosome, in particular if atomic-resolution crystal structures or models of individual components of the assembly can be placed into the density map. The present work introduces a novel algorithm termed BCL::EM-Fit that accurately fits atomic-detail structural models into medium resolution density maps. In an initial step, a "geometric hashing" algorithm provides a short list of likely placements. In a follow up Monte Carlo/Metropolis refinement step, the initial placements are optimized by their cross correlation coefficient. The resolution of density maps for a reliable fit was determined to be 10 Å or better using tests with simulated density maps. The algorithm was applied to fitting of capsid proteins into an experimental cryoEM density map of human adenovirus at a resolution of 6.8 and 9.0 Å, and fitting of the GroEL protein at 5.4 Å. In the process, the handedness of the cryoEM density map was unambiguously identified. The BCL::EM-Fit algorithm offers an alternative to the established Fourier/Real space fitting programs. BCL::EM-Fit is free for academic use and available from a web server or as downloadable binary file at http://www.meilerlab.org.
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