Abstract
BackgroundThe total number of known three-dimensional protein structures is rapidly increasing. Consequently, the need for fast structural search against complete databases without a significant loss of accuracy is increasingly demanding. Recently, TopSearch, an ultra-fast method for finding rigid structural relationships between a query structure and the complete Protein Data Bank (PDB), at the multi-chain level, has been released. However, comparable accurate flexible structural aligners to perform efficient whole database searches of multi-domain proteins are not yet available. The availability of such a tool is critical for a sustainable boosting of biological discovery.ResultsHere we report on the development of a new method for the fast and flexible comparison of protein structure chains. The method relies on the calculation of 2D matrices containing a description of the three-dimensional arrangement of secondary structure elements (angles and distances). The comparison involves the matching of an ensemble of substructures through a nested-two-steps dynamic programming algorithm. The unique features of this new approach are the integration and trade-off balancing of the following: 1) speed, 2) accuracy and 3) global and semiglobal flexible structure alignment by integration of local substructure matching. The comparison, and matching with competitive accuracy, of one medium sized (250-aa) query structure against the complete PDB database (216,322 protein chains) takes about 8 min using an average desktop computer. The method is at least 2–3 orders of magnitude faster than other tested tools with similar accuracy. We validate the performance of the method for fold and superfamily assignment in a large benchmark set of protein structures. We finally provide a series of examples to illustrate the usefulness of this method and its application in biological discovery.ConclusionsThe method is able to detect partial structure matching, rigid body shifts, conformational changes and tolerates substantial structural variation arising from insertions, deletions and sequence divergence, as well as structural convergence of unrelated proteins.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-015-0866-8) contains supplementary material, which is available to authorized users.
Highlights
The total number of known three-dimensional protein structures is rapidly increasing
By optimization of the different combinations of these parameters, we found that the best results were obtained with a C constant value of 45 and a gap-opening penalty of −4 for both steps of dynamic programming (Additional file 1: Table S1)
We have developed a new structural comparison algorithm based on the spatial arrangement of secondary structure elements and shown that it allows the efficient retrieval of similar folding patterns in database searches
Summary
The total number of known three-dimensional protein structures is rapidly increasing. TopSearch, an ultra-fast method for finding rigid structural relationships between a query structure and the complete Protein Data Bank (PDB), at the multi-chain level, has been released. Comparable accurate flexible structural aligners to perform efficient whole database searches of multi-domain proteins are not yet available. The availability of such a tool is critical for a sustainable boosting of biological discovery. Since the determination of the first structures in the 1970s to the present day, the number of solved protein structures in the Protein Data Bank (PDB) has continued to grow at an exponential rate, with more than one hundred thousand structures available today. The rise in number of known structures makes the comparison of query structures against the database increasingly costly (both for time and computational requirements) using existing tools. Residue-based methods are generally more accurate [16]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.