Circular Permutation in Proteins

This is a ‘‘Topic Page’ ’ article for PLoS Computational Biology. Circular permutation describes a type of relationship between proteins, whereby the proteins have a changed order of amino acids in their protein sequence, such that the sequence of the first portion of one protein (adjacent to the N-terminus) is related to that of the second portion of the other protein (near its C-terminus), and vice versa (see Figure 1). This is directly analogous to the mathematical notion of a cyclic permutation over the set of residues in a protein. Circular permutation can be the result of evolutionary events, post-translational modifications, or artificially engineered mutations. The result is a protein structure with different connectivity, but overall similar three-dimensional (3D) shape. The homology between portions of the proteins can be established by observing similar sequences between N- and C-terminal portions of the tw

Online assessment of ALS functional rating scale compares well to in-clinic evaluation: A prospective trial

Self-assessment of symptom progression in chronic diseases is of increasing importance in clinical research, patient management and specialized outpatient care. Against this background, we developed a secure internet platform (ALShome.de) that allows online assessment of the revised ALS Functional Rating Scale (ALSFRS-R) and other established self-assessment questionnaires. We developed a secure and closed internet portal to assess patient reported outcomes. In a prospective, controlled and stratified study, patients conducted a web-based self-assessment of ALSFRS-R compared to on-site assessment. On-site and online assessments were compared at baseline (n = 127) and after 3.5 months (n = 81, 64%). Results showed that correlation between on-site evaluation and online testing of ALSFRS-R was highly significant (r = 0.96; p < 0.001). The agreement of both capturing methods (online vs. on-site) was excellent (mean interval, 8.8 days). The adherence to online rating was high; 75% of patients tested on-site completed a follow-up online visit (mean 3.5 months, SD 1.7). We conclude that online self-assessment of ALS severity complements the well-established face-to-face application of the ALSFRS-R during on-site visits. The results of our study support the use of online administration of ALSFRS-R within clinical trials and for managing the care of ALS patients

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality

Molql : towards a common general purpose molecular query language

Advances in experimental techniques are providing access to ever more complex and larger macromolecular data sets. Definition and extraction of substructures represents a crucial step required for both analysis and visualization of these data. A common language for defining macromolecular substructures would streamline this step, and enable communication among different computational and visualization tools. However, software tools usually define their own query language or support a language that is not sufficiently general to describe complex spatial and other relationships within macromolecular structures. Herein, we introduce the Molecular Query Language (MolQL), a declarative language for describing substructures within molecular data. The design of the language has three main goals: 1) Make it easy for tool developers to implement the specification; 2) Be expressive enough to describe a wide range of molecular substructures; and 3) Be readily extensible. We describe the initial specification of the language, and provide its reference implementation that can execute MolQL expressions on any Protein Data Bank archival entry (pdb.org) and immediately show the result in a web browser. Moreover, we demonstrate the versatility of the language by translating Jmol, PyMOL, and VMD selection expressions into MolQL. Find out more about MolQL and try it online at http://molql.org/

Molql: Towards a Common General Purpose Molecular Query Language

Advances in experimental techniques are providing access to ever more complex and larger macromolecular data sets. Definition and extraction of substructures represents a crucial step required for both analysis and visualization of these data. A common language for defining macromolecular substructures would streamline this step, and enable communication among different computational and visualization tools. However, software tools usually define their own query language or support a language that is not sufficiently general to describe complex spatial and other relationships within macromolecular structures. Herein, we introduce the Molecular Query Language (MolQL), a declarative language for describing substructures within molecular data. The design of the language has three main goals: 1) Make it easy for tool developers to implement the specification; 2) Be expressive enough to describe a wide range of molecular substructures; and 3) Be readily extensible. We describe the initial specification of the language, and provide its reference implementation that can execute MolQL expressions on any Protein Data Bank archival entry (pdb.org) and immediately show the result in a web browser. Moreover, we demonstrate the versatility of the language by translating Jmol, PyMOL, and VMD selection expressions into MolQL. Find out more about MolQL and try it online at http://molql.org/

Systematic detection of internal symmetry in proteins using CE-Symm.

Symmetry is an important feature of protein tertiary and quaternary structures that has been associated with protein folding, function, evolution, and stability. Its emergence and ensuing prevalence has been attributed to gene duplications, fusion events, and subsequent evolutionary drift in sequence. This process maintains structural similarity and is further supported by this study. To further investigate the question of how internal symmetry evolved, how symmetry and function are related, and the overall frequency of internal symmetry, we developed an algorithm, CE-Symm, to detect pseudo-symmetry within the tertiary structure of protein chains. Using a large manually curated benchmark of 1007 protein domains, we show that CE-Symm performs significantly better than previous approaches. We use CE-Symm to build a census of symmetry among domain superfamilies in SCOP and note that 18% of all superfamilies are pseudo-symmetric. Our results indicate that more domains are pseudo-symmetric than previously estimated. We establish a number of recurring types of symmetry-function relationships and describe several characteristic cases in detail. With the use of the Enzyme Commission classification, symmetry was found to be enriched in some enzyme classes but depleted in others. CE-Symm thus provides a methodology for a more complete and detailed study of the role of symmetry in tertiary protein structure [availability: CE-Symm can be run from the Web at http://source.rcsb.org/jfatcatserver/symmetry.jsp. Source code and software binaries are also available under the GNU Lesser General Public License (version 2.1) at https://github.com/rcsb/symmetry. An interactive census of domains identified as symmetric by CE-Symm is available from http://source.rcsb.org/jfatcatserver/scopResults.jsp]