Published online 10 June 2010 Nucleic Acids Research, 2010, Vol. 38, Web Server issue W53–W58 doi:10.1093/nar/gkq522 ProteinDBS v2.0: a web server for global and local protein structure search Chi-Ren Shyu1,2,*, Bin Pang 1 , Pin-Hao Chi2, Nan Zhao 1 , Dmitry Korkin1,2 and Dong Xu1,2 1Informatics Institute and 2Department of Computer Science, University of Missouri, Columbia, MO 65211, USA Received February 24, 2010; Revised April 26, 2010; Accepted May 24, 2010 ABSTRACT ProteinDBS v2.0 is a web server designed for effi- cient and accurate comparisons and searches of structurally similar proteins from a large-scale database. It provides two comparison methods, global-to-global and local-to-local, to facilitate the searches of protein structures or substructures. ProteinDBS v2.0 applies advanced feature extrac- tion algorithms and scalable indexing techniques to achieve a high-running speed while preserving reasonably high precision of structural comparison. The experimental results show that our system is able to return results of global comparisons in seconds from a complete Protein Data Bank (PDB) database of 152 959 protein chains and that it takes much less time to complete local comparisons from a non-redundant database of 3276 proteins than other accurate comparison methods. ProteinDBS v2.0 supports query by PDB protein ID and by new structures uploaded by users. To our knowledge, this is the only search engine that can simultan- eously support global and local comparisons. ProteinDBS v2.0 is a useful tool to investigate func- tional or evolutional relationships among proteins. Moreover, the common substructures identified by local comparison can be potentially used to assist the human curation process in discovering new domains or folds from the ever-growing protein structure databases. The system is hosted at http://ProteinDBS.rnet.missouri.edu. INTRODUCTION The great demand for an eﬃcient and accurate search engine for 3D protein structures has continued to rise due to the dramatic increase in protein structural data and the role of protein structures in biological ﬁndings (1). The number of known protein structures in the primary structural database, the Protein Data Bank (PDB), had reached 63 271 ( 152 959 protein chain struc- tures) as of 16 February 2010, and is expected to continue growing at a high rate. The most important and diﬃcult task in handling such a large number of protein structures is to develop an eﬃcient and accurate tool for fast com- parison between a new structure and all existing ones in the database, so as to discover potential biological con- nections. To assist in this task, a high-throughput and accurate structural comparison method is essential. Traditional comparison methods, such as DALI (2) and CE (3), are based on the calculation of a distance matrix of residues, which can provide accurate alignment but are usually computationally expensive. In recent years, approaches have been developed to improve the performance of structural comparison and search. Fast web servers, including TOPSCAN (4), YAKUSA (5), 3D-Blast (6) and iSARST (7) map protein structures into 1D sequences and then use various sequence alignment methods to align two struc- tures. These approaches exhibit good eﬃciency; however, 1D representations of 3D structures potentially lose details of structural topologies, which could lead to lower accuracy than the accurate structural comparison methods (6). To meet the challenges of strict eﬃciency and accuracy requirements from the large-scale protein structure database, ProteinDBS was initially developed in 2003 to provide the community a real-time web server for searching globally similar protein structures (8). The ﬁrst generation of ProteinDBS has been widely used by the community and recognized by the 3 September 2004, issue of Science (9). During these years, ProteinDBS has been continuously improved in performance and service to keep it as a useful resource to study protein structures. In the new version of ProteinDBS, major advancements include local structural comparison as well as biologist-friendly query interfaces and visualization tools. In contrast to the global comparison, which tries to superimpose most of the corresponding backbone atoms from two proteins, the local comparison seeks to ﬁnd all common substructures between two proteins. As an example, gap-free common substructures are usually *To whom correspondence should be addressed. Tel: +1 573 882 3884; Fax: +1 573 884 8709; Email: shyuc@missouri.edu The Author(s) 2010. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.