Title PFfit: Polar Fast Fourier Matched Alignment of Atomistic Structures with 3D Electron Microscopy Maps

There continue to be increasing occurrences of both atomistic structure models in the PDB (possibly reconstructed from X-ray diffraction or NMR data), and 3D reconstructed cryo-electron microscopy (3D EM) maps (albeit at coarser resolution) of the same or homologous molecule or molecular assembly, deposited in the EMDB. To obtain the best possible structural model of the molecule at the best achievable resolution, and without any missing gaps, one typically aligns (match and fits) the atomistic structure model with the 3D EM map. We discuss a new algorithm and generalized framework, named PFfit (Polar Fast Fourier Fitting) for the best possible structural alignment of atomistic structures with 3D EM . While PFfit enables only a rigid, six dimensional (6D) alignment method, it augments prior work on 6D X-ray structure and 3D EM alignment in multiple ways: Scoring. PFfit includes a new scoring scheme that, in addition to rewarding overlaps between the volumes occupied by the atomistic structure and 3D EM map, penalizes overlaps between the volumes complementary to them. We quantitatively demonstrate how this new complementary scoring scheme improves upon existing approaches. PFfit also includes two scoring functions, the non-uniform exterior penalty and the skeleton-secondary structure score, and implements the scattering potential score as an alternative to traditional Gaussian blurring. Search. PFfit utilizes a fast search scheme of PFcorr [1], whose main advantage is the ability to search over uniformly and adaptively sampled subsets of the space of rigid-body motions. PFfit also implements a new reranking search and scoring methodology that considerably improves alignment metrics in results obtained from the initial search. The PFfit software package along with a tutorial is free for academic users and available through our website: http://www.ices.utexas.edu/CVC/software/.