A Structural-informatics Approach for Mining β-Sheets: Locating Sheets in Intermediate-resolution Density Maps

Here, we report a new computational method, called sheetminer, for mining β-sheets in the density maps at intermediate resolutions of 6 to 10 Å. The method employs a multi-step ad hoc morphological analysis of density maps to identify the unique characteristics of β-sheets. It was tested on density maps from 12 protein crystal structures that were artificially blurred to intermediate resolutions. There are a total of 35 independent β-sheets with a wide distribution of morphology. The method successfully located 34 of them and missed only one. The method was also applied to an experimental 9 Å electron cryomicroscopic structure and an 8 Å X-ray density map. In both cases, the sheet-searching results were found to agree very well with known high-resolution crystal structures. Collectively, these results demonstrate clearly the robustness of sheetminer in locating the regions belonging to β-sheets in the intermediate-resolution density maps. Furthermore, sheetminer is completely complementary to all other existing computational methods, including helixhunter and threading algorithms. Their combined usage has the potential to significantly enhance the computational modeling capacity for a much more complete interpretation of structural data at intermediate resolutions, from which extraction of functional information would be more effective. This is particularly important in the field of structural genomics, in which the fast screening approach may not always yield crystals that diffract to atomic resolution. An exciting future application of sheetminer is as a valuable tool for revealing the structures of amyloid fibrils that are rich in β-motifs.