Critical assessment of methods of protein structure prediction: Progress and new directions in round XI

Modeling of protein structure from amino acid sequence now plays a major role in structural biology. Here we report new developments and progress from the CASP11 community experiment, assessing the state of the art in structure modeling. Notable points include the following: (1) New methods for predicting three dimensional contacts resulted in a few spectacular template free models in this CASP, whereas models based on sequence homology to proteins with experimental structure continue to be the most accurate. (2) Refinement of initial protein models, primarily using molecular dynamics related approaches, has now advanced to the point where the best methods can consistently (though slightly) improve nearly all models. (3) The use of relatively sparse NMR constraints dramatically improves the accuracy of models, and another type of sparse data, chemical crosslinking, introduced in this CASP, also shows promise for producing better models. (4) A new emphasis on modeling protein complexes, in collaboration with CAPRI, has produced interesting results, but also shows the need for more focus on this area. (5) Methods for estimating the accuracy of models have advanced to the point where they are of considerable practical use. (6) A first assessment demonstrates that models can sometimes successfully address biological questions that motivate experimental structure determination. (7) There is continuing progress in accuracy of modeling regions of structure not directly available by comparative modeling, while there is marginal or no progress in some other areas

doi:10.1093/nar/gkp471 Stochastic noise in splicing machinery

The number of known alternative human isoforms has been increasing steadily with the amount of available transcription data. To date, over 100 000 isoforms have been detected in EST libraries, and at least 75 % of human genes have at least one alternative isoform. In this paper, we propose that most alternative splicing events are the result of noise in the splicing process. We show that the number of isoforms and their abundance can be predicted by a simple stochastic noise model that takes into account two factors: the number of introns in a gene and the expression level of a gene. The results strongly support the hypothesis that most alternative splicing is a consequence o

The Product Guides the Process: Discovering Disease Mechanisms

The nature of the product to be discovered guides the reasoning to discover it. Biologists and medical researchers often search for mechanisms. The "new mechanistic philosophy of science" provides resources about the nature of biological mechanisms that aid the discovery of mechanisms. Here, we apply these resources to the discovery of mechanisms in medicine. A new diagrammatic representation of a disease mechanism chain indicates both what is known and, most significantly, what is not known at a given time, thereby guiding the researcher and collaborators in discovery. Mechanisms of genetic diseases provide the examples

The Product Guides the Process: Discovering Disease Mechanisms

The nature of the product to be discovered guides the reasoning to discover it. Biologists and medical researchers often search for mechanisms. The "new mechanistic philosophy of science" provides resources about the nature of biological mechanisms that aid the discovery of mechanisms. Here, we apply these resources to the discovery of mechanisms in medicine. A new diagrammatic representation of a disease mechanism chain indicates both what is known and, most significantly, what is not known at a given time, thereby guiding the researcher and collaborators in discovery. Mechanisms of genetic diseases provide the examples

Assessment of protein disorder region predictions in CASP10

A systematic analysis of intrinsic disorder in proteins started at the turn of the century1–4 and still remains a hot research topic.5 Only this year several papers covering general aspects of protein disorder have been published5– 9 and the discussion on the fundamental principles of disorder continues to unfold.10,11 PubMed search with the keywords “intrinsically disordered protein 2012” and “intrinsically disordered protein 2013” returned 525 and 305 entries, respectively (as of April 2013). The number of experimentally verified intrinsically disordered proteins and regions is steadily increasing. The DisProt database12 currently contains annotations for 684 intrinsically disordered proteins, 1513 disordered regions, and describes 38 different biological functions associated with disordered regions. The more recently established IDEAL database also has a number of useful annotations on disordered proteins.13 Such a high interest in this area of research triggered rapid development of computational methods for prediction of the location of disordered regions in proteins. The recently published reviews and assessment papers14–18 altogether provide a comprehensive analysis of more than fifty disorder prediction methods. An independent assessment of the protein disorder methods within the scope of CASP started in 2002 and is now already in its sixth round.18–22 This study analyzes the results obtained by the 28 disorder prediction groups participating in CASP10

Evaluation of template-based models in CASP8 with standard measures

The strategy for evaluating template-based models submitted to CASP has continuously evolved from CASP1 to CASP5, leading to a standard procedure that has been used in all subsequent editions. The established approach includes methods for calculating the quality of each individual model, for assigning scores based on the distribution of the results for each target and for computing the statistical significance of the differences in scores between prediction methods. These data are made available to the assessor of the template-based modeling category, who uses them as a starting point for further evaluations and analyses. This article describes the detailed workflow of the procedure, provides justifications for a number of choices that are customarily made for CASP data evaluation, and reports the results of the analysis of template-based predictions at CASP8

SNPs3D: Candidate gene and SNP selection for association studies

The relationship between disease susceptibility and genetic variation is complex, and many different types of data are relevant. We describe a web resource and database that provides and integrates as much information as possible on disease/gene relationships at the molecular level. The resource http://www.SNPs3D.org has three primary modules. One module identifies which genes are candidates for involvement in a specified disease. A second module provides information about the relationships between sets of candidate genes. The third module analyzes the likely impact of non-synonymous SNPs on protein function. Disease/candidate gene relationships and gene-gene relationships are derived from the literature using simple but effective text profiling. SNP/protein function relationships are derived by two methods, one using principles of protein structure and stability, the other based on sequence conservation. Entries for each gene include a number of links to other data, such as expression profiles, pathway context, mouse knockout information and papers. Gene-gene interactions are presented in an interactive graphical interface, providing rapid access to the underlying information, as well as convenient navigation through the network. Use of the resource is illustrated with aspects of the inflammatory response and hypertension. The combination of SNP impact analysis, a knowledge based network of gene relationships and candidate genes, and access to a wide range of data and literature allow a user to quickly assimilate available information, and so develop models of gene-pathway-disease interaction.https://doi.org/10.1186/1471-2105-7-16