Alignment of protein sequences by their profiles.

Mission Bay Genentech Hall, University of California, San Francisco, San Francisco, CA 94143, USA.
Protein Science (Impact Factor: 2.74). 05/2004; 13(4):1071-87. DOI: 10.1110/ps.03379804
Source: PubMed

ABSTRACT The accuracy of an alignment between two protein sequences can be improved by including other detectably related sequences in the comparison. We optimize and benchmark such an approach that relies on aligning two multiple sequence alignments, each one including one of the two protein sequences. Thirteen different protocols for creating and comparing profiles corresponding to the multiple sequence alignments are implemented in the SALIGN command of MODELLER. A test set of 200 pairwise, structure-based alignments with sequence identities below 40% is used to benchmark the 13 protocols as well as a number of previously described sequence alignment methods, including heuristic pairwise sequence alignment by BLAST, pairwise sequence alignment by global dynamic programming with an affine gap penalty function by the ALIGN command of MODELLER, sequence-profile alignment by PSI-BLAST, Hidden Markov Model methods implemented in SAM and LOBSTER, pairwise sequence alignment relying on predicted local structure by SEA, and multiple sequence alignment by CLUSTALW and COMPASS. The alignment accuracies of the best new protocols were significantly better than those of the other tested methods. For example, the fraction of the correctly aligned residues relative to the structure-based alignment by the best protocol is 56%, which can be compared with the accuracies of 26%, 42%, 43%, 48%, 50%, 49%, 43%, and 43% for the other methods, respectively. The new method is currently applied to large-scale comparative protein structure modeling of all known sequences.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Residue depth accurately measures burial and parameterizes local protein environment. Depth is the distance of any atom/residue to the closest bulk water. We consider the non-bulk waters to occupy cavities, whose volumes are determined using a Voronoi procedure. Our estimation of cavity sizes is statistically superior to estimates made by CASTp and VOIDOO, and on par with McVol over a data set of 40 cavities. Our calculated cavity volumes correlated best with the experimentally determined destabilization of 34 mutants from five proteins. Some of the cavities identified are capable of binding small molecule ligands. In this study, we have enhanced our depth-based predictions of binding sites by including evolutionary information. We have demonstrated that on a database (LigASite) of ∼200 proteins, we perform on par with ConCavity and better than MetaPocket 2.0. Our predictions, while less sensitive, are more specific and precise. Finally, we use depth (and other features) to predict pKas of GLU, ASP, LYS and HIS residues. Our results produce an average error of just <1 pH unit over 60 predictions. Our simple empirical method is statistically on par with two and superior to three other methods while inferior to only one. The DEPTH server ( is an ideal tool for rapid yet accurate structural analyses of protein structures.
    Nucleic Acids Research 06/2013; · 8.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: ModBase ( is a database of annotated comparative protein structure models. The models are calculated by ModPipe, an automated modeling pipeline that relies primarily on Modeller for fold assignment, sequence-structure alignment, model building and model assessment ( ModBase currently contains almost 30 million reliable models for domains in 4.7 million unique protein sequences. ModBase allows users to compute or update comparative models on demand, through an interface to the ModWeb modeling server ( ModBase models are also available through the Protein Model Portal ( Recently developed associated resources include the AllosMod server for modeling ligand-induced protein dynamics (, the AllosMod-FoXS server for predicting a structural ensemble that fits an SAXS profile (, the FoXSDock server for protein-protein docking filtered by an SAXS profile (, the SAXS Merge server for automatic merging of SAXS profiles ( and the Pose & Rank server for scoring protein-ligand complexes ( In this update, we also highlight two applications of ModBase: a PSI:Biology initiative to maximize the structural coverage of the human alpha-helical transmembrane proteome and a determination of structural determinants of human immunodeficiency virus-1 protease specificity.
    Nucleic Acids Research 11/2013; · 8.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The comparative modeling approach to protein structure prediction inherently relies on a template structure. Before building a model such a template protein has to be found and aligned with the query sequence. Any error made on this stage may dramatically affects the quality of result. There is a need, therefore, to develop accurate and sensitive alignment protocols. BioShell threading software is a versatile tool for aligning protein structures, protein sequences or sequence profiles and query sequences to a template structures. The software is also capable of suboptimal alignment generation. It can be executed as an application from the UNIX command line, or as a set of Java classes called from a script or a Java application. The implemented Monte Carlo search engine greatly facilitates the development and benchmarking of new alignment scoring schemes evenwhen the functions exhibit non-deterministic polynomial-time complexity. Numerical experiments indicate that the new threading application offers template detection abilities and provides much better alignments than other methods. The package along with documentation and examples is available at:
    BMC Bioinformatics 01/2014; 15(1):22. · 3.02 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014