Electron cryomicroscopy is a fast developing technique aiming at the determination of the 3-dimensional structures of large protein complexes. Using this technique, protein density maps can be generated with 6 to 10 Å resolution. At such resolutions, the secondary structure elements such as helices and β-strands appear to be skeletons and can be computationally detected. However, it is not known which segment of the protein sequence corresponds to which of the skeletons. The topology in this paper refers to the linear order and the directionality of the secondary structures. For a protein with N helices and M strands, there are ( N!2 N )( M!2 M ) different topologies, each of which maps N helix segments and M strand segments on the protein sequence to N helix and M strand skeletons. Since the backbone position is not available in the skeleton, each topology of the skeletons corresponds to additional freedom to position the atoms in the skeletons.
We have developed a method to construct the possible atomic structures for the helix skeletons by sampling the solution space of all the possible topologies of the skeletons. Our method also ranks the possible structures based on the contact energy formed by the secondary structures, rather than the entire chain. If we assume that the backbone atomic positions are known for the skeletons, then the native topology of the secondary structures can be found in the top 30% of the ranked list of all possible topologies for all the 30 proteins tested, and within the top 5% for most of the 30 proteins. Without assuming the backbone location of the skeletons, the possible atomic structures of the skeletons can be constructed using the axis of the skeleton and the sequence segments. The best constructed structure for the skeletons has RMSD to native between 4 and 5 Å for the four tested α-proteins. These best constructed structures were ranked the 17 th, 31 st, 16 th and 5 th respectively for the four proteins out of 32066, 391833, 98755 and 192935 possible assignments in the pool.