3D – MOSAIC : An integrative method for computational modeling of large multimolecular complexes.
Modeling large multi-molecular assemblies at atomic resolution is a key task in elucidating cell function. Since, there is no single experimental method, that can deliver atomic resolution structures of such large molecules, hybrid methods, which integrate data from various experimental modalities, are being developed for this task.
We have developed a new integrative method, which combines atomic resolution models of individual assembly components with an electron microscopy map of the full assembly. It can also naturally accommodate available chemical cross link (Xlink) data.
Specifically, the input to our algorithm is an intermediate resolution (6-10 Angstrom) electron density map of the full assembly, atomic resolution (2 A0) maps of the individual assembly subunits, and, if available, cross link information between some residues of neighboring subunits (an Xlink can be visualized as a loose ~30A0 string connecting two atoms on the surfaces of neighboring subunits). The output is an atomic resolution map of the whole assembly.
The algorithm was highly successful and efficient on all the intermediate resolution EM complexes from the 2010 Cryo-EM Modeling Challenge. Remarkably, a 6.8A0 resolution 20S proteasome map, consisting of 28 (structurally homologues) units was modeled at 1.5A0 RMSD from native in about 10 minutes on a Core i7 laptop. In case of missing (or poorly modeled) individual subunits, the method can return partial solutions, thus, enabling interactive modeling.
From a purely geometric viewpoint, the task can be viewed as an assembly of a large multiple piece puzzle, where we have relatively accurate models of the individual subunits, and a rough, low resolution scan of the full puzzle volume.
This is joint work with my M.Sc. students Dan Cohen and Naama Amir.
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