Analyzing the symmetrical arrangement of structural repeats in proteins with CE-Symm

Many proteins fold into highly regular and repetitive three dimensional structures. The analysis of structural patterns and repeated elements is fundamental to understand protein function and evolution. We present recent improvements to the CE-Symm tool for systematically detecting and analyzing the internal symmetry and structural repeats in proteins. In addition to the accurate detection of internal symmetry, the tool is now capable of i) reporting the type of symmetry, ii) identifying the smallest repeating unit, iii) describing the arrangement of repeats with transformation operations and symmetry axes, and iv) comparing the similarity of all the internal repeats at the residue level. CE-Symm 2.0 helps the user investigate proteins with a robust and intuitive sequence-to-structure analysis, with many applications in protein classification, functional annotation and evolutionary studies. We describe the algorithmic extensions of the method and demonstrate its applications to the study of interesting cases of protein evolution

SISYPHUS—structural alignments for proteins with non-trivial relationships

With the increasing amount of structural data, the number of homologous protein structures bearing topological irregularities is steadily growing. These include proteins with circular permutations, segment-swapping, context-dependent folding or chameleon sequences that can adopt alternative secondary structures. Their non-trivial structural relationships are readily identified during expert analysis but their automatic identification using the existing computational tools still remains difficult or impossible. Such non-trivial cases of protein relationships are known to pose a problem to multiple alignment algorithms and to impede comparative modeling studies. They support a new emerging concept of evolutionary changeable protein fold, which creates practical difficulties for the hierarchical classifications of protein structures.To facilitate the understanding of, and to provide a comprehensive annotation of proteins with such non-trivial structural relationships we have created SISYPHUS ([Σισυϕος]—in Greek crafty), a compendium to the SCOP database. The SISYPHUS database contains a collection of manually curated structural alignments and their inter-relationships. The multiple alignments are constructed for protein structural regions that range from oligomeric biological units, or individual domains to fragments of different size. The SISYPHUS multiple alignments are displayed with SPICE, a browser that provides an integrated view of protein sequences, structures and their annotations. The database is available from

Chaste: an open source C++ library for computational physiology and biology

Chaste - Cancer, Heart And Soft Tissue Environment - is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has been driven by two initial applications: cardiac electrophysiology and cancer development. A large number of cardiac electrophysiology studies have been enabled and performed, including high performance computational investigations of defibrillation on realistic human cardiac geometries. New models for the initiation and growth of tumours have been developed. In particular, cell-based simulations have provided novel insight into the role of stem cells in the colorectal crypt. Chaste is constantly evolving and is now being applied to a far wider range of problems. The code provides modules for handling common scientific computing components, such as meshes and solvers for ordinary and partial differential equations (ODEs/PDEs). Re-use of these components avoids the need for researchers to "re-invent the wheel" with each new project, accelerating the rate of progress in new applications. Chaste is developed using industrially-derived techniques, in particular test-driven development, to ensure code quality, re-use and reliability. In this article we provide examples that illustrate the types of problems Chaste can be used to solve, which can be run on a desktop computer. We highlight some scientific studies that have used or are using Chaste, and the insights they have provided. The source code, both for specific releases and the development version, is available to download under an open source Berkeley Software Distribution (BSD) licence at http://www.cs.ox.ac.uk/chaste, together with details of a mailing list and links to documentation and tutorials

Recon3D enables a three-dimensional view of gene variation in human metabolism

Genome-scale network reconstructions have helped uncover the molecular basis of metabolism. Here we present Recon3D, a computational resource that includes three-dimensional (3D) metabolite and protein structure data and enables integrated analyses of metabolic functions in humans. We use Recon3D to functionally characterize mutations associated with disease, and identify metabolic response signatures that are caused by exposure to certain drugs. Recon3D represents the most comprehensive human metabolic network model to date, accounting for 3,288 open reading frames (representing 17% of functionally annotated human genes), 13,543 metabolic reactions involving 4,140 unique metabolites, and 12,890 protein structures. These data provide a unique resource for investigating molecular mechanisms of human metabolism. Recon3D is available at http://vmh.life

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

ProteinHistorian: Tools for the Comparative Analysis of Eukaryote Protein Origin

The evolutionary history of a protein reflects the functional history of its ancestors. Recent phylogenetic studies identified distinct evolutionary signatures that characterize proteins involved in cancer, Mendelian disease, and different ontogenic stages. Despite the potential to yield insight into the cellular functions and interactions of proteins, such comparative phylogenetic analyses are rarely performed, because they require custom algorithms. We developed ProteinHistorian to make tools for performing analyses of protein origins widely available. Given a list of proteins of interest, ProteinHistorian estimates the phylogenetic age of each protein, quantifies enrichment for proteins of specific ages, and compares variation in protein age with other protein attributes. ProteinHistorian allows flexibility in the definition of protein age by including several algorithms for estimating ages from different databases of evolutionary relationships. We illustrate the use of ProteinHistorian with three example analyses. First, we demonstrate that proteins with high expression in human, compared to chimpanzee and rhesus macaque, are significantly younger than those with human-specific low expression. Next, we show that human proteins with annotated regulatory functions are significantly younger than proteins with catalytic functions. Finally, we compare protein length and age in many eukaryotic species and, as expected from previous studies, find a positive, though often weak, correlation between protein age and length. ProteinHistorian is available through a web server with an intuitive interface and as a set of command line tools; this allows biologists and bioinformaticians alike to integrate these approaches into their analysis pipelines. ProteinHistorian's modular, extensible design facilitates the integration of new datasets and algorithms. The ProteinHistorian web server, source code, and pre-computed ages for 32 eukaryotic genomes are freely available under the GNU public license at http://lighthouse.ucsf.edu/ProteinHistorian/

BEAST 2:A Software Platform for Bayesian Evolutionary Analysis

We present a new open source, extensible and flexible software platform for Bayesian evolutionary analysis called BEAST 2. This software platform is a re-design of the popular BEAST 1 platform to correct structural deficiencies that became evident as the BEAST 1 software evolved. Key among those deficiencies was the lack of post-deployment extensibility. BEAST 2 now has a fully developed package management system that allows third party developers to write additional functionality that can be directly installed to the BEAST 2 analysis platform via a package manager without requiring a new software release of the platform. This package architecture is showcased with a number of recently published new models encompassing birth-death-sampling tree priors, phylodynamics and model averaging for substitution models and site partitioning. A second major improvement is the ability to read/write the entire state of the MCMC chain to/from disk allowing it to be easily shared between multiple instances of the BEAST software. This facilitates checkpointing and better support for multi-processor and high-end computing extensions. Finally, the functionality in new packages can be easily added to the user interface (BEAUti 2) by a simple XML template-based mechanism because BEAST 2 has been re-designed to provide greater integration between the analysis engine and the user interface so that, for example BEAST and BEAUti use exactly the same XML file format

GA4GH: International policies and standards for data sharing across genomic research and healthcare.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits