MOTIVATION: Rapid methods for protein structure search enable biological discoveries based on flexibly defined structural similarity, unleashing the power of the ever greater number of solved protein structures. Projection methods show promise for the development of fast structural database search solutions. Projection methods map a structure to a point in a high-dimensional space and compare two structures by measuring distance between their projected points. These methods offer a tremendous increase in speed over residue-level structural alignment methods. However, current projection methods are not practical, partly because they are unable to identify local similarities. RESULTS: We propose a new projection-based approach that can rapidly detect global as well as local structural similarities. Local structural search is enabled by a topology-inspired writhe decomposition protocol that produces a small number of fragments while ensuring that similar structures are cut in a similar manner. In benchmark tests, we show that our method, writher, improves accuracy over existing projection methods in terms of recognizing scop domains out of multi-domain proteins, while maintaining accuracy comparable with existing projection methods in a standard single-domain benchmark test. AVAILABILITY: The source code is available at the following website: http://compbio.berkeley.edu/proj/writher/.

Cryo-EM has become an increasingly powerful technique for elucidating the structure, dynamics, and function of large flexible macromolecule assemblies that cannot be determined at atomic resolution. However, due to the relatively low resolution of cryo-EM data, a major challenge is to identify components of complexes appearing in cryo-EM maps. Here, we describe EMatch, a novel integrated approach for recognizing structural homologues of protein domains present in a 6-10 A resolution cryo-EM map and constructing a quasi-atomic structural model of their assembly. The method is highly efficient and has been successfully validated on various simulated data. The strength of the method is demonstrated by a domain assembly of an experimental cryo-EM map of native GroEL at 6 A resolution.