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Natural language processing, Precision oncology, Controlled natural language, Nanopublication, Treatment reasoning, Rapid learning, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), and QH301-705.5

Abstract Background We describe a prototype implementation of a platform that could underlie a Precision Oncology Rapid Learning system. Results We describe the prototype platform, and examine some important issues and details. In the Appendix we provide a complete walk-through of the prototype platform. Conclusions The design choices made in this implementation rest upon ten constitutive hypotheses, which, taken together, define a particular view of how a rapid learning medical platform might be defined, organized, and implemented.

FASTA sequences, NEWICK tree, Sequence alignments, UNIX utilities, BioPerl, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), and QH301-705.5

Abstract Background Automated bioinformatics workflows are more robust, easier to maintain, and results more reproducible when built with command-line utilities than with custom-coded scripts. Command-line utilities further benefit by relieving bioinformatics developers to learn the use of, or to interact directly with, biological software libraries. There is however a lack of command-line utilities that leverage popular Open Source biological software toolkits such as BioPerl (http://bioperl.org) to make many of the well-designed, robust, and routinely used biological classes available for a wider base of end users. Results Designed as standard utilities for UNIX-family operating systems, BpWrapper makes functionality of some of the most popular BioPerl modules readily accessible on the command line to novice as well as to experienced bioinformatics practitioners. The initial release of BpWrapper includes four utilities with concise command-line user interfaces, bioseq, bioaln, biotree, and biopop, specialized for manipulation of molecular sequences, sequence alignments, phylogenetic trees, and DNA polymorphisms, respectively. Over a hundred methods are currently available as command-line options and new methods are easily incorporated. Performance of BpWrapper utilities lags that of precompiled utilities while equivalent to that of other utilities based on BioPerl. BpWrapper has been tested on BioPerl Release 1.6, Perl versions 5.10.1 to 5.25.10, and operating systems including Apple macOS, Microsoft Windows, and GNU/Linux. Release code is available from the Comprehensive Perl Archive Network (CPAN) at https://metacpan.org/pod/Bio::BPWrapper. Source code is available on GitHub at https://github.com/bioperl/p5-bpwrapper. Conclusions BpWrapper improves on existing sequence utilities by following the design principles of Unix text utilities such including a concise user interface, extensive command-line options, and standard input/output for serialized operations. Further, dozens of novel methods for manipulation of sequences, alignments, and phylogenetic trees, unavailable in existing utilities (e.g., EMBOSS, Newick Utilities, and FAST), are provided. Bioinformaticians should find BpWrapper useful for rapid prototyping of workflows on the command-line without creating custom scripts for comparative genomics and other bioinformatics applications.

Base Sequence, Sequence Alignment, Computational Biology methods, Phylogeny, and Software

Background: Automated bioinformatics workflows are more robust, easier to maintain, and results more reproducible when built with command-line utilities than with custom-coded scripts. Command-line utilities further benefit by relieving bioinformatics developers to learn the use of, or to interact directly with, biological software libraries. There is however a lack of command-line utilities that leverage popular Open Source biological software toolkits such as BioPerl ( http://bioperl.org ) to make many of the well-designed, robust, and routinely used biological classes available for a wider base of end users.
Results: Designed as standard utilities for UNIX-family operating systems, BpWrapper makes functionality of some of the most popular BioPerl modules readily accessible on the command line to novice as well as to experienced bioinformatics practitioners. The initial release of BpWrapper includes four utilities with concise command-line user interfaces, bioseq, bioaln, biotree, and biopop, specialized for manipulation of molecular sequences, sequence alignments, phylogenetic trees, and DNA polymorphisms, respectively. Over a hundred methods are currently available as command-line options and new methods are easily incorporated. Performance of BpWrapper utilities lags that of precompiled utilities while equivalent to that of other utilities based on BioPerl. BpWrapper has been tested on BioPerl Release 1.6, Perl versions 5.10.1 to 5.25.10, and operating systems including Apple macOS, Microsoft Windows, and GNU/Linux. Release code is available from the Comprehensive Perl Archive Network (CPAN) at https://metacpan.org/pod/Bio::BPWrapper . Source code is available on GitHub at https://github.com/bioperl/p5-bpwrapper .
Conclusions: BpWrapper improves on existing sequence utilities by following the design principles of Unix text utilities such including a concise user interface, extensive command-line options, and standard input/output for serialized operations. Further, dozens of novel methods for manipulation of sequences, alignments, and phylogenetic trees, unavailable in existing utilities (e.g., EMBOSS, Newick Utilities, and FAST), are provided. Bioinformaticians should find BpWrapper useful for rapid prototyping of workflows on the command-line without creating custom scripts for comparative genomics and other bioinformatics applications.

Algorithms, Education, Medical, Humans, Publications, Medical Oncology, Precision Medicine, and Software

Background: We describe a prototype implementation of a platform that could underlie a Precision Oncology Rapid Learning system.
Results: We describe the prototype platform, and examine some important issues and details. In the Appendix we provide a complete walk-through of the prototype platform.
Conclusions: The design choices made in this implementation rest upon ten constitutive hypotheses, which, taken together, define a particular view of how a rapid learning medical platform might be defined, organized, and implemented.

Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), and QH301-705.5

Abstract Background Successful realization of a "systems biology" approach to analyzing cells is a grand challenge for our understanding of life. However, current modeling approaches to cell simulation are labor-intensive, manual affairs, and therefore constitute a major bottleneck in the evolution of computational cell biology. Results We developed the Genome-based Modeling (GEM) System for the purpose of automatically prototyping simulation models of cell-wide metabolic pathways from genome sequences and other public biological information. Models generated by the GEM System include an entire Escherichia coli metabolism model comprising 968 reactions of 1195 metabolites, achieving 100% coverage when compared with the KEGG database, 92.38% with the EcoCyc database, and 95.06% with iJR904 genome-scale model. Conclusion The GEM System prototypes qualitative models to reduce the labor-intensive tasks required for systems biology research. Models of over 90 bacterial genomes are available at our web site.

Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), and QH301-705.5

Abstract Background Recent years have seen the emergence of genome annotation methods based on the phylo-grammar, a probabilistic model combining continuous-time Markov chains and stochastic grammars. Previously, phylo-grammars have required considerable effort to implement, limiting their adoption by computational biologists. Results We have developed an open source software tool, xrate, for working with reversible, irreversible or parametric substitution models combined with stochastic context-free grammars. xrate efficiently estimates maximum-likelihood parameters and phylogenetic trees using a novel "phylo-EM" algorithm that we describe. The grammar is specified in an external configuration file, allowing users to design new grammars, estimate rate parameters from training data and annotate multiple sequence alignments without the need to recompile code from source. We have used xrate to measure codon substitution rates and predict protein and RNA secondary structures. Conclusion Our results demonstrate that xrate estimates biologically meaningful rates and makes predictions whose accuracy is comparable to that of more specialized tools.

Databases, Genetic, Genomics, Information Systems, Internet, Phenotype, User-Computer Interface, Computational Biology methods, and Software

Background: There is a huge demand on bioinformaticians to provide their biologists with user friendly and scalable software infrastructures to capture, exchange, and exploit the unprecedented amounts of new *omics data. We here present MOLGENIS, a generic, open source, software toolkit to quickly produce the bespoke MOLecular GENetics Information Systems needed.
Methods: The MOLGENIS toolkit provides bioinformaticians with a simple language to model biological data structures and user interfaces. At the push of a button, MOLGENIS' generator suite automatically translates these models into a feature-rich, ready-to-use web application including database, user interfaces, exchange formats, and scriptable interfaces. Each generator is a template of SQL, JAVA, R, or HTML code that would require much effort to write by hand. This 'model-driven' method ensures reuse of best practices and improves quality because the modeling language and generators are shared between all MOLGENIS applications, so that errors are found quickly and improvements are shared easily by a re-generation. A plug-in mechanism ensures that both the generator suite and generated product can be customized just as much as hand-written software.
Results: In recent years we have successfully evaluated the MOLGENIS toolkit for the rapid prototyping of many types of biomedical applications, including next-generation sequencing, GWAS, QTL, proteomics and biobanking. Writing 500 lines of model XML typically replaces 15,000 lines of hand-written programming code, which allows for quick adaptation if the information system is not yet to the biologist's satisfaction. Each application generated with MOLGENIS comes with an optimized database back-end, user interfaces for biologists to manage and exploit their data, programming interfaces for bioinformaticians to script analysis tools in R, Java, SOAP, REST/JSON and RDF, a tab-delimited file format to ease upload and exchange of data, and detailed technical documentation. Existing databases can be quickly enhanced with MOLGENIS generated interfaces using the 'ExtractModel' procedure.
Conclusions: The MOLGENIS toolkit provides bioinformaticians with a simple model to quickly generate flexible web platforms for all possible genomic, molecular and phenotypic experiments with a richness of interfaces not provided by other tools. All the software and manuals are available free as LGPLv3 open source at http://www.molgenis.org.

Computer Simulation, Genome, Bacterial genetics, Pilot Projects, Protein Interaction Mapping methods, Chromosome Mapping methods, Escherichia coli physiology, Escherichia coli Proteins metabolism, Gene Expression Regulation physiology, Models, Biological, Signal Transduction physiology, and Software

Background: Successful realization of a "systems biology" approach to analyzing cells is a grand challenge for our understanding of life. However, current modeling approaches to cell simulation are labor-intensive, manual affairs, and therefore constitute a major bottleneck in the evolution of computational cell biology.
Results: We developed the Genome-based Modeling (GEM) System for the purpose of automatically prototyping simulation models of cell-wide metabolic pathways from genome sequences and other public biological information. Models generated by the GEM System include an entire Escherichia coli metabolism model comprising 968 reactions of 1195 metabolites, achieving 100% coverage when compared with the KEGG database, 92.38% with the EcoCyc database, and 95.06% with iJR904 genome-scale model.
Conclusion: The GEM System prototypes qualitative models to reduce the labor-intensive tasks required for systems biology research. Models of over 90 bacterial genomes are available at our web site.

Conserved Sequence, Phylogeny, Algorithms, Artificial Intelligence, Chromosome Mapping methods, Sequence Alignment methods, Sequence Analysis, DNA methods, and Software

Background: Recent years have seen the emergence of genome annotation methods based on the phylo-grammar, a probabilistic model combining continuous-time Markov chains and stochastic grammars. Previously, phylo-grammars have required considerable effort to implement, limiting their adoption by computational biologists.
Results: We have developed an open source software tool, xrate, for working with reversible, irreversible or parametric substitution models combined with stochastic context-free grammars. xrate efficiently estimates maximum-likelihood parameters and phylogenetic trees using a novel "phylo-EM" algorithm that we describe. The grammar is specified in an external configuration file, allowing users to design new grammars, estimate rate parameters from training data and annotate multiple sequence alignments without the need to recompile code from source. We have used xrate to measure codon substitution rates and predict protein and RNA secondary structures.
Conclusion: Our results demonstrate that xrate estimates biologically meaningful rates and makes predictions whose accuracy is comparable to that of more specialized tools.

Cell Line, Tumor, Humans, K562 Cells, Cluster Analysis, and Computational Biology

Background: Cluster heatmaps are commonly used in biology and related fields to reveal hierarchical clusters in data matrices. This visualization technique has high data density and reveal clusters better than unordered heatmaps alone. However, cluster heatmaps have known issues making them both time consuming to use and prone to error. We hypothesize that visualization techniques without the rigid grid constraint of cluster heatmaps will perform better at clustering-related tasks.
Results: We developed an approach to "unbox" the heatmap values and embed them directly in the hierarchical clustering results, allowing us to use standard hierarchical visualization techniques as alternatives to cluster heatmaps. We then tested our hypothesis by conducting a survey of 45 practitioners to determine how cluster heatmaps are used, prototyping alternatives to cluster heatmaps using pair analytics with a computational biologist, and evaluating those alternatives with hour-long interviews of 5 practitioners and an Amazon Mechanical Turk user study with approximately 200 participants. We found statistically significant performance differences for most clustering-related tasks, and in the number of perceived visual clusters. Visit git.io/vw0t3 for our results.
Conclusions: The optimal technique varied by task. However, gapmaps were preferred by the interviewed practitioners and outperformed or performed as well as cluster heatmaps for clustering-related tasks. Gapmaps are similar to cluster heatmaps, but relax the heatmap grid constraints by introducing gaps between rows and/or columns that are not closely clustered. Based on these results, we recommend users adopt gapmaps as an alternative to cluster heatmaps.

Computational Biology methods, Computer Communication Networks, Models, Biological, Programming Languages, Software, and User-Computer Interface

Background: Matlab, a powerful and productive language that allows for rapid prototyping, modeling and simulation, is widely used in computational biology. Modeling and simulation of large biological systems often require more computational resources then are available on a single computer. Existing distributed computing environments like the Distributed Computing Toolbox, MatlabMPI, Matlab*G and others allow for the remote (and possibly parallel) execution of Matlab commands with varying support for features like an easy-to-use application programming interface, load-balanced utilization of resources, extensibility over the wide area network, and minimal system administration skill requirements. However, all of these environments require some level of access to participating machines to manually distribute the user-defined libraries that the remote call may invoke.
Results: mGrid augments the usual process distribution seen in other similar distributed systems by adding facilities for user code distribution. mGrid's client-side interface is an easy-to-use native Matlab toolbox that transparently executes user-defined code on remote machines (i.e. the user is unaware that the code is executing somewhere else). Run-time variables are automatically packed and distributed with the user-defined code and automated load-balancing of remote resources enables smooth concurrent execution. mGrid is an open source environment. Apart from the programming language itself, all other components are also open source, freely available tools: light-weight PHP scripts and the Apache web server.
Conclusion: Transparent, load-balanced distribution of user-defined Matlab toolboxes and rapid prototyping of many simple parallel applications can now be done with a single easy-to-use Matlab command. Because mGrid utilizes only Matlab, light-weight PHP scripts and the Apache web server, installation and configuration are very simple. Moreover, the web-based infrastructure of mGrid allows for it to be easily extensible over the Internet.

Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), and QH301-705.5

Abstract Background Matlab, a powerful and productive language that allows for rapid prototyping, modeling and simulation, is widely used in computational biology. Modeling and simulation of large biological systems often require more computational resources then are available on a single computer. Existing distributed computing environments like the Distributed Computing Toolbox, MatlabMPI, Matlab*G and others allow for the remote (and possibly parallel) execution of Matlab commands with varying support for features like an easy-to-use application programming interface, load-balanced utilization of resources, extensibility over the wide area network, and minimal system administration skill requirements. However, all of these environments require some level of access to participating machines to manually distribute the user-defined libraries that the remote call may invoke. Results mGrid augments the usual process distribution seen in other similar distributed systems by adding facilities for user code distribution. mGrid's client-side interface is an easy-to-use native Matlab toolbox that transparently executes user-defined code on remote machines (i.e. the user is unaware that the code is executing somewhere else). Run-time variables are automatically packed and distributed with the user-defined code and automated load-balancing of remote resources enables smooth concurrent execution. mGrid is an open source environment. Apart from the programming language itself, all other components are also open source, freely available tools: light-weight PHP scripts and the Apache web server. Conclusion Transparent, load-balanced distribution of user-defined Matlab toolboxes and rapid prototyping of many simple parallel applications can now be done with a single easy-to-use Matlab command. Because mGrid utilizes only Matlab, light-weight PHP scripts and the Apache web server, installation and configuration are very simple. Moreover, the web-based infrastructure of mGrid allows for it to be easily extensible over the Internet.

Algorithms, Electronic Data Processing, Peptide Fragments, Peptides chemistry, Peptides analysis, Software, and Tandem Mass Spectrometry methods

Background: Protein identification using mass spectrometry is an important tool in many areas of the life sciences, and in proteomics research in particular. Increasing the number of proteins correctly identified is dependent on the ability to include new knowledge about the mass spectrometry fragmentation process, into computational algorithms designed to separate true matches of peptides to unidentified mass spectra from spurious matches. This discrimination is achieved by computing a function of the various features of the potential match between the observed and theoretical spectra to give a numerical approximation of their similarity. It is these underlying "metrics" that determine the ability of a protein identification package to maximise correct identifications while limiting false discovery rates. There is currently no software available specifically for the simple implementation and analysis of arbitrary novel metrics for peptide matching and for the exploration of fragmentation patterns for a given dataset.
Results: We present Harvest: an open source software tool for analysing fragmentation patterns and assessing the power of a new piece of information about the MS/MS fragmentation process to more clearly differentiate between correct and random peptide assignments. We demonstrate this functionality using data metrics derived from the properties of individual datasets in a peptide identification context. Using Harvest, we demonstrate how the development of such metrics may improve correct peptide assignment confidence in the context of a high-throughput proteomics experiment and characterise properties of peptide fragmentation.
Conclusions: Harvest provides a simple framework in C++ for analysing and prototyping metrics for peptide matching, the core of the protein identification problem. It is not a protein identification package and answers a different research question to packages such as Sequest, Mascot, X!Tandem, and other protein identification packages. It does not aim to maximise the number of assigned peptides from a set of unknown spectra, but instead provides a method by which researchers can explore fragmentation properties and assess the power of novel metrics for peptide matching in the context of a given experiment. Metrics developed using Harvest may then become candidates for later integration into protein identification packages.

Algorithms, Mass Spectrometry methods, Programming Languages, and Software

Background: Mass spectrometry is an essential analytical technique for high-throughput analysis in proteomics and metabolomics. The development of new separation techniques, precise mass analyzers and experimental protocols is a very active field of research. This leads to more complex experimental setups yielding ever increasing amounts of data. Consequently, analysis of the data is currently often the bottleneck for experimental studies. Although software tools for many data analysis tasks are available today, they are often hard to combine with each other or not flexible enough to allow for rapid prototyping of a new analysis workflow.
Results: We present OpenMS, a software framework for rapid application development in mass spectrometry. OpenMS has been designed to be portable, easy-to-use and robust while offering a rich functionality ranging from basic data structures to sophisticated algorithms for data analysis. This has already been demonstrated in several studies.
Conclusion: OpenMS is available under the Lesser GNU Public License (LGPL) from the project website at http://www.openms.de.

Biomedical Research organization administration, Documentation methods, Information Storage and Retrieval methods, Internationality, Neurosciences organization administration, Research organization administration, Semantics, Biomedical Research methods, Databases, Factual, Information Dissemination methods, Internet, Natural Language Processing, Neurosciences methods, and Research Design

Background: A fundamental goal of the U.S. National Institute of Health (NIH) "Roadmap" is to strengthen Translational Research, defined as the movement of discoveries in basic research to application at the clinical level. A significant barrier to translational research is the lack of uniformly structured data across related biomedical domains. The Semantic Web is an extension of the current Web that enables navigation and meaningful use of digital resources by automatic processes. It is based on common formats that support aggregation and integration of data drawn from diverse sources. A variety of technologies have been built on this foundation that, together, support identifying, representing, and reasoning across a wide range of biomedical data. The Semantic Web Health Care and Life Sciences Interest Group (HCLSIG), set up within the framework of the World Wide Web Consortium, was launched to explore the application of these technologies in a variety of areas. Subgroups focus on making biomedical data available in RDF, working with biomedical ontologies, prototyping clinical decision support systems, working on drug safety and efficacy communication, and supporting disease researchers navigating and annotating the large amount of potentially relevant literature.
Results: We present a scenario that shows the value of the information environment the Semantic Web can support for aiding neuroscience researchers. We then report on several projects by members of the HCLSIG, in the process illustrating the range of Semantic Web technologies that have applications in areas of biomedicine.
Conclusion: Semantic Web technologies present both promise and challenges. Current tools and standards are already adequate to implement components of the bench-to-bedside vision. On the other hand, these technologies are young. Gaps in standards and implementations still exist and adoption is limited by typical problems with early technology, such as the need for a critical mass of practitioners and installed base, and growing pains as the technology is scaled up. Still, the potential of interoperable knowledge sources for biomedicine, at the scale of the World Wide Web, merits continued work.

Computational Biology methods, Computer Simulation, Models, Molecular, Predictive Value of Tests, Thermodynamics, Protein Structure, Secondary, and Software

Background: The protein structure prediction problem is one of the most challenging problems in biological sciences. Many approaches have been proposed using database information and/or simplified protein models. The protein structure prediction problem can be cast in the form of an optimization problem. Notwithstanding its importance, the problem has very seldom been tackled by Constraint Logic Programming, a declarative programming paradigm suitable for solving combinatorial optimization problems.
Results: Constraint Logic Programming techniques have been applied to the protein structure prediction problem on the face-centered cube lattice model. Molecular dynamics techniques, endowed with the notion of constraint, have been also exploited. Even using a very simplified model, Constraint Logic Programming on the face-centered cube lattice model allowed us to obtain acceptable results for a few small proteins. As a test implementation their (known) secondary structure and the presence of disulfide bridges are used as constraints. Simplified structures obtained in this way have been converted to all atom models with plausible structure. Results have been compared with a similar approach using a well-established technique as molecular dynamics.
Conclusions: The results obtained on small proteins show that Constraint Logic Programming techniques can be employed for studying protein simplified models, which can be converted into realistic all atom models. The advantage of Constraint Logic Programming over other, much more explored, methodologies, resides in the rapid software prototyping, in the easy way of encoding heuristics, and in exploiting all the advances made in this research area, e.g. in constraint propagation and its use for pruning the huge search space.

Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), and QH301-705.5

Abstract Background A fundamental goal of the U.S. National Institute of Health (NIH) "Roadmap" is to strengthen Translational Research, defined as the movement of discoveries in basic research to application at the clinical level. A significant barrier to translational research is the lack of uniformly structured data across related biomedical domains. The Semantic Web is an extension of the current Web that enables navigation and meaningful use of digital resources by automatic processes. It is based on common formats that support aggregation and integration of data drawn from diverse sources. A variety of technologies have been built on this foundation that, together, support identifying, representing, and reasoning across a wide range of biomedical data. The Semantic Web Health Care and Life Sciences Interest Group (HCLSIG), set up within the framework of the World Wide Web Consortium, was launched to explore the application of these technologies in a variety of areas. Subgroups focus on making biomedical data available in RDF, working with biomedical ontologies, prototyping clinical decision support systems, working on drug safety and efficacy communication, and supporting disease researchers navigating and annotating the large amount of potentially relevant literature. Results We present a scenario that shows the value of the information environment the Semantic Web can support for aiding neuroscience researchers. We then report on several projects by members of the HCLSIG, in the process illustrating the range of Semantic Web technologies that have applications in areas of biomedicine. Conclusion Semantic Web technologies present both promise and challenges. Current tools and standards are already adequate to implement components of the bench-to-bedside vision. On the other hand, these technologies are young. Gaps in standards and implementations still exist and adoption is limited by typical problems with early technology, such as the need for a critical mass of practitioners and installed base, and growing pains as the technology is scaled up. Still, the potential of interoperable knowledge sources for biomedicine, at the scale of the World Wide Web, merits continued work.

Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), and QH301-705.5

Abstract Background Mass spectrometry is an essential analytical technique for high-throughput analysis in proteomics and metabolomics. The development of new separation techniques, precise mass analyzers and experimental protocols is a very active field of research. This leads to more complex experimental setups yielding ever increasing amounts of data. Consequently, analysis of the data is currently often the bottleneck for experimental studies. Although software tools for many data analysis tasks are available today, they are often hard to combine with each other or not flexible enough to allow for rapid prototyping of a new analysis workflow. Results We present OpenMS, a software framework for rapid application development in mass spectrometry. OpenMS has been designed to be portable, easy-to-use and robust while offering a rich functionality ranging from basic data structures to sophisticated algorithms for data analysis. This has already been demonstrated in several studies. Conclusion OpenMS is available under the Lesser GNU Public License (LGPL) from the project website at http://www.openms.de.

Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), and QH301-705.5

Abstract Background The protein structure prediction problem is one of the most challenging problems in biological sciences. Many approaches have been proposed using database information and/or simplified protein models. The protein structure prediction problem can be cast in the form of an optimization problem. Notwithstanding its importance, the problem has very seldom been tackled by Constraint Logic Programming, a declarative programming paradigm suitable for solving combinatorial optimization problems. Results Constraint Logic Programming techniques have been applied to the protein structure prediction problem on the face-centered cube lattice model. Molecular dynamics techniques, endowed with the notion of constraint, have been also exploited. Even using a very simplified model, Constraint Logic Programming on the face-centered cube lattice model allowed us to obtain acceptable results for a few small proteins. As a test implementation their (known) secondary structure and the presence of disulfide bridges are used as constraints. Simplified structures obtained in this way have been converted to all atom models with plausible structure. Results have been compared with a similar approach using a well-established technique as molecular dynamics. Conclusions The results obtained on small proteins show that Constraint Logic Programming techniques can be employed for studying protein simplified models, which can be converted into realistic all atom models. The advantage of Constraint Logic Programming over other, much more explored, methodologies, resides in the rapid software prototyping, in the easy way of encoding heuristics, and in exploiting all the advances made in this research area, e.g. in constraint propagation and its use for pruning the huge search space.