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Sequence alignments are models that capture the structural, functional and evolutionary relationships between proteins. Structure-guided sequence alignments are helpful in the case of distantly related proteins with poor sequence identity, thus rendering routine sequence alignment methods ineffective. Protein Alignment organized as Structural Superfamilies or PASS2 database provides such sequence alignments of protein domains within a superfamily as per the Structural Classification of Proteins extended (SCOPe) database. The current update of PASS2 (i.e. PASS2.7) is following the latest release of SCOPe (2.07) and we provide data for 14 323 protein domains that are <40% identical and are organized into 2024 superfamilies. Several useful features derived from the alignments, such as conserved secondary structural motifs, HMMs and residues conserved across the superfamily, are also reported. Protein domains that are deviant from the rest of the members of a superfamily may compromise the quality of the alignment, and we found this to be the case in ∼7% of the total superfamilies we considered. To improve the alignment by objectively identifying such 'outliers', in this update, we have used a k-means-based unsupervised machine learning method for clustering superfamily members, where features provided were length of domains aligned, Cα-RMSD derived from the rigid-body superposition of all members and gaps contributed to the alignment by each domain. In a few cases, we have split the superfamily as per the clusters predicted and provided complete data for each cluster. A new feature included in this update is absolutely conserved interactions (ACIs) between residue backbones and side chains, which are obtained by aligning protein structure networks using structure-guided sequence alignments of superfamilies. ACIs provide valuable information about functionally important residues and the structure-function relationships of proteins. The ACIs and the corresponding conserved networks for backbone and sidechain have been marked on the superimposed structure separately.
DATABASE URL: The updated version of the PASS2 database is available at http://caps.ncbs.res.in/pass2/.

The number of protein structures is increasing due to the individual initiatives and rapid development of structure determination techniques. Structure-based sequence alignments of distantly related proteins enable the investigation of structural, evolutionary and functional relationships between proteins and their domains leading to their common evolutionary origin. Protein Alignments organized as Structural Superfamilies (PASS2) is a database that provides such alignments of members of protein domain superfamilies of known structure and with less than 40% sequence identity. PASS2 has been continuously updated in accordance to Structural Classification of Proteins (SCOP), and now Structural Classification of Proteins - extended (SCOPe). The current update directly corresponds to SCOPe 2.06, dealing with 2006 domain superfamilies of known structure and about 14 000 domains. Alignments have been augmented by features such as hidden Markov models, highly conserved residues, structural motifs and gene ontology terms, which are available for download. In this update, we introduce the concepts of 'extreme structural outliers' and 'split superfamilies' as well.

Structure-based sequence alignment is an essential step in assessing and analysing the relationship of distantly related proteins. PASS2 is a database that records such alignments for protein domain superfamilies and has been constantly updated periodically. This update of the PASS2 version, named as PASS2.5, directly corresponds to the SCOPe 2.04 release. All SCOPe structural domains that share less than 40% sequence identity, as defined by the ASTRAL compendium of protein structures, are included. The current version includes 1977 superfamilies and has been assembled utilizing the structure-based sequence alignment protocol. Such an alignment is obtained initially through MATT, followed by a refinement through the COMPARER program. The JOY program has been used for structural annotations of such alignments. In this update, we have automated the protocol and focused on inclusion of new features such as mapping of GO terms, absolutely conserved residues among the domains in a superfamily and inclusion of PDBs, that are absent in SCOPe 2.04, using the HMM profiles from the alignments of the superfamily members and are provided as a separate list. We have also implemented a more user-friendly manner of data presentation and options for downloading more features. PASS2.5 version is available at http://caps.ncbs.res.in/pass2/.

Accurate structure-based sequence alignments of distantly related proteins are crucial in gaining insight about protein domains that belong to a superfamily. The PASS2 database provides alignments of proteins related at the superfamily level and are characterized by low sequence identity. We thus report an automated, updated version of the superfamily alignment database known as PASS2.4, consisting of 1961 superfamilies and 10,569 protein domains, which is in direct correspondence with SCOP (1.75) database. Database organization, improved methods for efficient structure-based sequence alignments and the analysis of extreme distantly related proteins within superfamilies formed the focus of this update. Alignment of family-specific functional residues can be realized using such alignments and is shown using one superfamily as an example. The database of alignments and other related features can be accessed at http://caps.ncbs.res.in/pass2/.

BACKGROUND: The functional selection and three-dimensional structural constraints of proteins in nature often relates to the retention of significant sequence similarity between proteins of similar fold and function despite poor sequence identity. Organization of structure-based sequence alignments for distantly related proteins, provides a map of the conserved and critical regions of the protein universe that is useful for the analysis of folding principles, for the evolutionary unification of protein families and for maximizing the information return from experimental structure determination. The Protein Alignment organised as Structural Superfamily (PASS2) database represents continuously updated, structural alignments for evolutionary related, sequentially distant proteins. DESCRIPTION: An automated and updated version of PASS2 is, in direct correspondence with SCOP 1.63, consisting of sequences having identity below 40% among themselves. Protein domains have been grouped into 628 multi-member superfamilies and 566 single member superfamilies. Structure-based sequence alignments for the superfamilies have been obtained using COMPARER, while initial equivalencies have been derived from a preliminary superposition using LSQMAN or STAMP 4.0. The final sequence alignments have been annotated for structural features using JOY4.0. The database is supplemented with sequence relatives belonging to different genomes, conserved spatially interacting and structural motifs, probabilistic hidden markov models of superfamilies based on the alignments and useful links to other databases. Probabilistic models and sensitive position specific profiles obtained from reliable superfamily alignments aid annotation of remote homologues and are useful tools in structural and functional genomics. PASS2 presents the phylogeny of its members both based on sequence and structural dissimilarities. Clustering of members allows us to understand diversification of the family members. The search engine has been improved for simpler browsing of the database. CONCLUSIONS: The database resolves alignments among the structural domains consisting of evolutionarily diverged set of sequences. Availability of reliable sequence alignments of distantly related proteins despite poor sequence identity and single-member superfamilies permit better sampling of structures in libraries for fold recognition of new sequences and for the understanding of protein structure-function relationships of individual superfamilies. PASS2 is accessible at http://www.ncbs.res.in/~faculty/mini/campass/pass2.html

PASS2 is a nearly automated version of CAMPASS and contains sequence alignments of proteins grouped at the level of superfamilies. This database has been created to fall in correspondence with SCOP database (1.53 release) and currently consists of 110 multi-member superfamilies and 613 superfamilies corresponding to single members. In multi-member superfamilies, protein chains with no more than 25% sequence identity have been considered for the alignment and hence the database aims to address sequence alignments which represent 26 219 protein domains under the SCOP 1.53 release. Structure-based sequence alignments have been obtained by COMPARER and the initial equivalences are provided automatically from a MALIGN alignment and subsequently augmented using STAMP4.0. The final sequence alignments have been annotated for the structural features using JOY4.0. Several interesting links are provided to other related databases and genome sequence relatives. Availability of reliable sequence alignments of distantly related proteins, despite poor sequence identity and single-member superfamilies, permit better sampling of structures in libraries for fold recognition of new sequences and for the understanding of protein structure-function relationships of individual superfamilies. The database can be queried by keywords and also by sequence search, interfaced by PSI-BLAST methods. Structure-annotated sequence alignments and several structural accessory files can be retrieved for all the superfamilies including the user-input sequence. The database can be accessed from http://www.ncbs.res.in/%7Efaculty/mini/campass/pass.html.