Frédéric Guyon

PEP-FOLD: an updated de novo structure prediction server for both linear and disulfide bonded cyclic peptides

In the context of the renewed interest of peptides as therapeutics, it is important to have an on-line resource for 3D structure prediction of peptides with well-defined structures in aqueous solution. We present an updated version of PEP-FOLD allowing the treatment of both linear and disulphide bonded cyclic peptides with 9–36 amino acids. The server makes possible to define disulphide bonds and any residue–residue proximity under the guidance of the biologists. Using a benchmark of 34 cyclic peptides with one, two and three disulphide bonds, the best PEP-FOLD models deviate by an average RMS of 2.75 Å from the full NMR structures. Using a benchmark of 37 linear peptides, PEP-FOLD locates lowest-energy conformations deviating by 3 Å RMS from the NMR rigid cores. The evolution of PEP-FOLD comes as a new on-line service to supersede the previous server. The server is available at: http://bioserv.rpbs.univ-paris-diderot.fr/PEP-FOLD.

Frog2: Efficient 3D conformation ensemble generator for small compounds

Frog is a web tool dedicated to small compound 3D generation. Here we present the new version, Frog2, which allows the generation of conformation ensembles of small molecules starting from either 1D, 2D or 3D description of the compounds. From a compound description in one of the SMILES, SDF or mol2 formats, the server will return an ensemble of diverse conformers generated using a two stage Monte Carlo approach in the dihedral space. When starting from 1D or 2D description of compounds, Frog2 is capable to detect the sites of ambiguous stereoisomery, and thus to sample different stereoisomers. Frog2 also embeds new energy minimization and ring generation facilities that solve the problem of some missing cycle structures in the Frog1 ring library. Finally, the optimized generator of conformation ensembles in Frog2 results in a gain of computational time permitting Frog2 to be up to 20 times faster that Frog1, while producing satisfactory conformations in terms of structural quality and conformational diversity. The high speed and the good quality of generated conformational ensembles makes it possible the treatment of larger compound collections using Frog2. The server and documentation are freely available at http://bioserv.rpbs.univ-paris-diderot.fr/Frog2.

Analysis of the copy number profiles of several tumor samples from the same patient reveals the successive steps in tumorigenesis

We present a computational method, TuMult, for reconstructing the sequence of copy number changes driving carcinogenesis, based on the analysis of several tumor samples from the same patient. We demonstrate the reliability of the method with simulated data, and describe applications to three different cancers, showing that TuMult is a valuable tool for the establishment of clonal relationships between tumor samples and the identification of chromosome aberrations occurring at crucial steps in cancer progression.

CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma†

The gene cyclin‐dependent kinase inhibitor 2A (CDKN2A) is frequently inactivated by deletion in bladder carcinoma. However, its role in bladder tumourigenesis remains unclear. We investigated the role of CDKN2A deletion in urothelial carcinogenesis, as a function of FGFR3 mutation status, a marker for one of the two pathways of bladder tumour progression, the Ta pathway. We studied 288 bladder carcinomas: 177 non‐muscle‐invasive (123 Ta, 54 T1) and 111 muscle‐invasive (T2–4) tumours. CDKN2A copy number was determined by multiplex ligation‐dependent probe amplification, and FGFR3 mutations by SNaPshot analysis. FGFR3 mutation was detected in 124 tumours (43.1%) and CDKN2A homozygous deletion in 56 tumours (19.4%). CDKN2A homozygous deletion was significantly more frequent in FGFR3‐mutated tumours than in wild‐type FGFR3 tumours (p = 0.0015). This event was associated with muscle‐invasive tumours within the FGFR3‐mutated subgroup (p < 0.0001) but not in wild‐type FGFR3 tumours. Similar findings were obtained for an independent series of 101 bladder carcinomas. The impact of CDKN2A deletions on recurrence‐free and progression‐free survival was then analysed in 89 patients with non‐muscle‐invasive FGFR3‐mutated tumours. Kaplan–Meier survival analysis showed that CDKN2A losses (hemizygous and homozygous) were associated with progression (p = 0.0002), but not with recurrence, in these tumours. Multivariate Cox regression analysis identified CDKN2A loss as a predictor of progression independent of stage and grade. These findings highlight the crucial role of CDKN2A loss in the progression of non‐muscle‐invasive FGFR3‐mutated bladder carcinomas and provide a potentially useful clinical marker for adapting the treatment of such tumours, which account for about 50% of cases at initial clinical presentation. Copyright

A proposal for a standard CORBA interface for genome maps.

MOTIVATION The scientific community urgently needs to standardize the exchange of biological data. This is helped by the use of a common protocol and the definition of shared data structures. We have based our standardization work on CORBA, a technology that has become a standard in the past years and allows interoperability between distributed objects. RESULTS We have defined an IDL specification for genome maps and present it to the scientific community. We have implemented CORBA servers based on this IDL to distribute RHdb and HuGeMap maps. The IDL will co-evolve with the needs of the mapping community. AVAILABILITY The standard IDL for genome maps is available at http:// corba.ebi.ac.uk/RHdb/EUCORBA/MapIDL.htm l. The IORs to browse maps from Infobiogen and EBI are at http://www.infobiogen.fr/services/Hugemap/IOR and http://corba.ebi.ac.uk/RHdb/EUCORBA/IOR CONTACT: manu@infobiogen.fr, tome@ebi.ac.uk

Fast protein fragment similarity scoring using a Binet–Cauchy kernel

MOTIVATION Meaningful scores to assess protein structure similarity are essential to decipher protein structure and sequence evolution. The mining of the increasing number of protein structures requires fast and accurate similarity measures with statistical significance. Whereas numerous approaches have been proposed for protein domains as a whole, the focus is progressively moving to a more local level of structure analysis for which similarity measurement still remains without any satisfactory answer. RESULTS We introduce a new score based on Binet-Cauchy kernel. It is normalized and bounded between 1-maximal similarity that implies exactly the same conformations for protein fragments-and -1-mirror image conformations, the unrelated conformations having a null mean score. This allows for the search of both similar and mirror conformations. In addition, such score addresses two major issue of the widely used root mean square deviation (RMSD). First, it achieves length independent statistics even for short fragments. Second, it shows better performance in the discrimination of medium range RMSD values. Being simpler and faster to compute than the RMSD, it also provides the means for large-scale mining of protein structures. AVAILABILITY AND IMPLEMENTATION The computer software implementing the score is available at http://bioserv.rpbs.univ-paris-diderot.fr/BCscore/ CONTACT frederic.guyon@univ-paris-diderot.fr SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Detecting Protein Candidate Fragments Using a Structural Alphabet Profile Comparison Approach

Predicting accurate fragments from sequence has recently become a critical step for protein structure modeling, as protein fragment assembly techniques are presently among the most efficient approaches for de novo prediction. A key step in these approaches is, given the sequence of a protein to model, the identification of relevant fragments - candidate fragments - from a collection of the available 3D structures. These fragments can then be assembled to produce a model of the complete structure of the protein of interest. The search for candidate fragments is classically achieved by considering local sequence similarity using profile comparison, or threading approaches. In the present study, we introduce a new profile comparison approach that, instead of using amino acid profiles, is based on the use of predicted structural alphabet profiles, where structural alphabet profiles contain information related to the 3D local shapes associated with the sequences. We show that structural alphabet profile-profile comparison can be used efficiently to retrieve accurate structural fragments, and we introduce a fully new protocol for the detection of candidate fragments. It identifies fragments specific of each position of the sequence and of size varying between 6 and 27 amino-acids. We find it outperforms present state of the art approaches in terms (i) of the accuracy of the fragments identified, (ii) the rate of true positives identified, while having a high coverage score. We illustrate the relevance of the approach on complete target sets of the two previous Critical Assessment of Techniques for Protein Structure Prediction (CASP) rounds 9 and 10. A web server for the approach is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/SAFrag.

HuGeMap: A Distributed and Integrated Human Genome Map Database

The HuGeMap database stores the major genetic and physical maps of the human genome. It is also interconnected with the gene radiation hybrid mapping database RHdb. HuGeMap is accessible through a Web server for interactive browsing at URL http://www.infobiogen. fr/services/Hugemap , as well as through a CORBA server for effective programming. HuGeMap is intended as an attempt to build open, interconnected databases, that is databases that distribute their objects worldwide in compliance with a recognized standard of distribution. Maps can be displayed and compared with a java applet (http://babbage.infobiogen.fr:15000/Mappet/Show. html ) that queries the HuGeMap ORB server as well as the RHdb ORB server at the EBI.

The HuGeMap Database: interconnection and visualization of human genome maps

The HuGeMap database stores the major genetic and physical maps of the human genome. HuGeMap is accessible on the Web at http://www. infobiogen.fr/services/Hugemap and through a CORBA server. A standard genome map data format for the interconnection of genome map databases was defined in collaboration with the EBI. The HuGeMap CORBA server provides this interconnection using the interface definition language IDL. Two graphical user interfaces were developed for the visualization of the HuGeMap data: ZoomMap (http://www.infobiogen.fr/services/zomit/Zoom Map.html) for navigation by zooming and data transformation via magic lenses, and MappetShow (http://www.infobiogen.fr/services/Mappet) for visualizing and comparing maps.

Assessing 3D scores for protein structure fragment mining

correspondence: Pierre Tuffery rPBs, Universite Paris Diderot-Paris 7, inserM UMr-s973 and F75205, Paris, France Tel +33 157 278 374 Fax +33 157 278 372 email pierre.tuffery@univ-paris-diderot.fr Abstract: Quantifying the 3D similarity between two proteins is a difficult task that has motivated the assessment of several 3D scores. New developments in protein modeling and analysis have led to the emergence of new interest towards mining structures at the local level. We assess in the context of fragment mining several dissimilarity scores. We revisit the concept of mirror conformation previously introduced at the level of complete structures and extend it to the more local level. We also consider an explicit criterion measuring the fragment boundary discrepancies. Whereas classical criteria such as the root mean square deviation (RMSd) fail to identify similar shapes in a consistent way, we show that local mirror and boundary mismatch filtering greatly supplements classical scores to select significant matches. The geometrical conditions defined by such criteria can be considered as signatures of fragment similarity. Furthermore, it is possible to tune the degree of similarity depending on the size of the mirrors accepted. This results in a more intuitive perception of the concept of similarity, and opens new perspectives for the rapid mining of large collections of structures.