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Cylindrical Similarity Measurement for Helices in Medium-Resolution Cryo-Electron Microscopy Density Maps.

ABSTRACT: Cryo-electron microscopy (cryo-EM) density maps at medium resolution (5-10 Å) reveal secondary structural features such as α-helices and β-sheets, but they lack the side chain details that would enable a direct structure determination. Among the more than 800 entries in the Electron Microscopy Data Bank (EMDB) of medium-resolution density maps that are associated with atomic models, a wide variety of similarities can be observed between maps and models. To validate such atomic models and to classify structural features, a local similarity criterion, the F₁ score, is proposed and evaluated in this study. The F₁ score is theoretically normalized to a range from zero to one, providing a local measure of cylindrical agreement between the density and atomic model of a helix. A systematic scan of 30,994 helices (among 3,247 protein chains modeled into medium-resolution density maps) reveals an actual range of observed F₁ scores from 0.171 to 0.848, suggesting that the cylindrical fit of the current data is well stratified by the proposed measure. The best (highest) F₁ scores tend to be associated with regions that exhibit high and spatially homogeneous local resolution (between 5 Å and 7.5 Å) in the helical density. The proposed F₁ scores can be used as a discriminative classifier for validation studies and as a ranking criterion for cryo-EM density features in databases.

SUBMITTER: Sazzed S

PROVIDER: S-EPMC8279803 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:X-ray crystallography and cryo-electron microscopy (cryo-EM) are complementary techniques for structure determination. Crystallography usually reveals more detailed information, while cryo-EM is an extremely useful technique for studying large-sized macromolecules. As the gap between the resolution of crystallography and cryo-EM data narrows, the cryo-EM map of a macromolecule could serve as an initial model to solve the phase problem of crystal diffraction for high-resolution structure determination. FSEARCH is a procedure to utilize the low-resolution molecular shape for crystallographic phasing. The IPCAS (Iterative Protein Crystal structure Automatic Solution) pipeline is an automatic direct-methods-aided dual-space iterative phasing and model-building procedure. When only an electron-density map is available as the starting point, IPCAS is capable of generating a completed model from the phases of the input map automatically, without the requirement of an initial model. In this study, a hybrid method integrating X-ray crystallography with cryo-EM to help with structure determination is presented. With a cryo-EM map as the starting point, the workflow of the method involves three steps. (1) Cryo-EM map replacement: FSEARCH is utilized to find the correct translation and orientation of the cryo-EM map in the crystallographic unit cell and generates the initial low-resolution map. (2) Phase extension: the phases calculated from the correctly placed cryo-EM map are extended to high-resolution X-ray data by non-crystallographic symmetry averaging with phenix.resolve. (3) Model building: IPCAS is used to generate an initial model using the phase-extended map and perform model completion by iteration. Four cases (the lowest cryo-EM map resolution being 6.9 Å) have been tested for the general applicability of the hybrid method, and almost complete models have been generated for all test cases with reasonable Rwork/Rfree. The hybrid method therefore provides an automated tool for X-ray structure determination using a cryo-EM map as the starting point.

Dataset Information

Cylindrical Similarity Measurement for Helices in Medium-Resolution Cryo-Electron Microscopy Density Maps.

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