Electron cryomicroscopy is becoming a major experimental technique in solving the structures of large molecular assemblies. More and more three-dimensional images have been obtained at the medium resolutions between 5 and 10 Å. At this resolution range, major α-helices can be detected as cylindrical sticks and β-sheets can be detected as plain-like regions. A critical question in de novo modeling from cryo-EM images is to determine the match between the detected secondary structures from the image and those on the protein sequence. We formulate this matching problem into a constrained graph problem and present an O(Δ(2)N(2)2(N)) algorithm to this NP-Hard problem. The algorithm incorporates the dynamic programming approach into a constrained K-shortest path algorithm. Our method, DP-TOSS, has been tested using α-proteins with maximum 33 helices and α-β proteins up to five helices and 12 β-strands. The correct match was ranked within the top 35 for 19 of the 20 α-proteins and all nine α-β proteins tested. The results demonstrate that DP-TOSS improves accuracy, time and memory space in deriving the topologies of the secondary structure elements for proteins with a large number of secondary structures and a complex skeleton.
Electron cryo-microscopy is a fast advancing biophysical technique to derive three-dimensional structures of large protein complexes. Using this technique, many density maps have been generated at intermediate resolution such as 6-10 Å resolution. Although it is challenging to derive the backbone of the protein directly from such density maps, secondary structure elements such as helices and β-sheets can be computationally detected. Our work in this paper provides an approach to enumerate the top-ranked possible topologies instead of enumerating the entire population of the topologies. This approach is particularly practical for large proteins. We developed a directed weighted graph, the topology graph, to represent the secondary structure assignment problem. We prove that the problem of finding the valid topology with the minimum cost is NP hard. We developed an O(N(2)2(N)) dynamic programming algorithm to identify the topology with the minimum cost. The test of 15 proteins suggests that our dynamic programming approach is feasible to work with proteins of much larger size than we could before. The largest protein in the test contains 18 helical sticks detected from the density map out of 33 helices in the protein.
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