Biomedical subjects

Jacques Chomilier

Publications and source records attributed to Jacques Chomilier.

8 recordsLinked to original sources

PubMed2005

Improvement of collagen-induced arthritis by active immunization against murine IL-1beta peptides designed by molecular modelling.

Interleukin-1beta (IL-1beta) is a crucial cytokine in inflammation processes and has been implicated in the pathogenesis of several chronic inflammatory diseases. Strategies designed to blocking IL-1beta by passive administration of inhibitors (mAbs, IL-1 receptor antagonist) have previously demonstrated efficacy in rheumatoid arthritis (RA). Using molecular modelling, we have defined three murine IL-1beta peptide regions characterized by their close proximity to the receptor. Synthetic peptides corresponding to these regions, in cyclic and linear form, were delivered as immunogens in Swiss mice, resulting in significant levels of autoantibodies directed against the native murine IL-1beta cytokine as determined by ELISA and by an assay for neutralization of IL-1beta biological activity. More importantly, one of the cyclic peptides showed a protective effect against inflammation and articular destruction in DBA/1 mouse collagen-induced arthritis, a model of RA. The high rate of success observed for active immunization against cytokine peptides in vivo suggests that the in silico approach to autoantigen design may be a promising avenue for the development of anti-cytokine immunotherapeutics.

Animals↗

PubMed2005

Filtering redundancies for sequence similarity search programs.

Database scanning programs such as BLAST and FASTA are used nowadays by most biologists for the post-genomic processing of DNA or protein sequence information (in particular to retrieve the structure/function of uncharacterized proteins). Unfortunately, their results can be polluted by identical alignments (called redundancies) coming from the same protein or DNA sequences present in different entries of the database. This makes the efficient use of the listed alignments difficult. Pretreatment of databases has been proposed to suppress strictly identical entries. However, there still remain many identical alignments since redundancies may occur locally for entries corresponding to various fragments of the same sequence or for entries corresponding to very homologous sequences but differing at the level of a few residues such as ortholog proteins. In the present work, we show that redundant alignments can be indeed numerous even when working with a pretreated non-redundant data bank, going as high as 60% of the output results according to the query and the bank. Therefore the accuracy and the efficiency of the post-genomic work will be greatly increased if these redundancies are removed. To solve this up to now unaddressed problem, we have developed an algorithm that allows for the efficient and safe suppression of all the redundancies with no loss of information. This algorithm is based on various filtering steps that we describe here in the context of the Automat similarity search program, and such an algorithm should also be added to the other similarity search programs (BLAST, FASTA, etc...).

Algorithms↗

PubMed2004

Identification of two immunogenic domains of the prion protein--PrP--which activate class II-restricted T cells and elicit antibody responses against the native molecule.

Recent reports suggest that immunity against the prion protein (PrP) retards transmissible spongiform encephalopathies progression in infected mice. A major obstacle to the development of vaccines comes from the fact that PrP is poorly immunogenic, as it is seen as self by the host immune system. Additional questions concern the immune mechanisms involved in protection and the risk of eliciting adverse reactions in the central nervous system of treated patients. Peptide-based vaccines offer an attractive strategy to overcome these difficulties. We have undertaken the identification of the immunogenic regions of PrP, which trigger helper T cells (Th) associated with antibody production. Our results identify two main regions, one between the structured and flexible portion of PrP (98-127) and a second between alpha 1 and alpha 2 helix (143-187). Peptides (30-mer) corresponding to these regions elicit class II-restricted Th cells and antibody production against native PrP and could therefore be of potential interest for a peptide-based vaccination.

Amino Acid Sequence↗

PubMed2004

Analysis of fragments induced by simulated lattice protein folding.

The folding process of a set of 42 proteins, representative of the various folds, has been simulated by means of a Monte Carlo method on a discrete lattice, using two different potentials of mean force. Multiple compact fragments of contiguous residues are formed in the simulation, stable in composition, but not in geometry. During time, the number of fragments decreases until one final compact globular state is reached. We focused on the early steps of the folding in order to evidence the maximum number of fragments, provided they are sufficiently stable in sequence. A correlation has been established between these proto fragments and regular secondary-structure elements, whatever their nature, alpha helices or beta strands. Quantitatively, this is revealed by an overall mean one-residue quality factor of nearly 60%, which is better for proteins mainly composed of alpha helices. The correspondence between the number of fragments and the number of secondary-structure elements is of 77% and the regions separating successive fragments are mainly located in loops. Besides, hydrophobic clusters deduced from HCA correspond to fragments with an equivalent accuracy. These results suggest that folding pathways do not contain structurally static intermediate. However, since the beginning of folding, most residues that will later form one given secondary structure are kept close in space by being involved in the same fragment. This aggregation may be a way to accelerate the formation of the native state and enforces the key role played by hydrophobic residues in the formation of the fragments, thus in the folding process itself.

Computer Simulation↗

PubMed2004

Universal positions in globular proteins.

The description of globular protein structures as an ensemble of contiguous 'closed loops' or 'tightened end fragments' reveals fold elements crucial for the formation of stable structures and for navigating the very process of protein folding. These are the ends of the loops, which are spatially close to each other but are situated apart in the polypeptide chain by 25-30 residues. They also correlate with the locations of highly conserved hydrophobic residues (referred to as topohydrophobic), in a structural alignment of the members of a protein family. This study analysed these positions in 111 representatives of different protein folds, and then carried out dynamic Monte Carlo simulations of the first steps of the folding process, aimed at predicting the origins of the assembling folds. The simulations demonstrated that there is an obvious trend for certain sets of residues, named 'mostly interacting residues', to be buried at the early stages of the folding process. Location of these residues at the loop ends and correlation with topohydrophobic positions are demonstrated, thereby giving a route to simulations of the protein folding process.

Amino Acid Sequence↗

PubMed2003

A new protein folding algorithm based on hydrophobic compactness: Rigid Unconnected Secondary Structure Iterative Assembly (RUSSIA). I: Methodology.

We present an algorithm that is able to propose compact models of protein 3D structures, only starting from the prediction of the nature and length of regular secondary structures. Helices are modeled by cylinders and sheets by helicoid surfaces, all strands of a sheet being considered as a single block. It means that relative topology of the strands inside one sheet is a prerequisite. Loops are only considered as constraints, given by the maximal distance between their Calpha extremities according to their sequence length. Unconnected regular secondary structures are reduced to a single point, the center of their hydrophobic faces. These centers are then repeatedly moved in order to obtain a compact hydrophobic core. To prevent secondary structures from interpenetrating, a repulsive term is introduced in the function whose minimization leads to the compact structure. This RUSSIA (Rigid Unconnected Secondary Structure Assembly) algorithm has the advantage of relying on a small number of variables and therefore many initial conformations can be tested. Flexibility is produced in the following way: helices or sheets are allowed to rotate around the direction leading to the center of the model; residues in a sheet can slide along the main direction of the strand where they are embedded. RUSSIA is fast and simple and it produces on a test set several neighbor good models with an r.m.s. to the native structures in the range 1.4-3.7 A. These models can be further treated by statistical potentials used in threading approaches in order to detect the best candidate. The limits of the present method are the following: small proteins with few secondary structures are excluded; multi domain proteins must be split into several compact globular domains from their sequences; sheets of more than five strands and completely buried helices are not treated. In this first paper the algorithm is developed and in Part II, which follows, some applications are presented and the program is evaluated.

Algorithms↗

PubMed2003

A new protein folding algorithm based on hydrophobic compactness: Rigid Unconnected Secondary Structure Iterative Assembly (RUSSIA). II: Applications.

The RUSSIA procedure (Rigid Unconnected Secondary Structure Iterative Assembly) produces structural models of cores of small- and medium-sized proteins. Loops are omitted from this treatment and regular secondary structures are reduced to points, the centers of their hydrophobic faces. This methodology relies on the maximum compactness of the hydrophobic residues, as described in detail in Part I. Starting data are the sequence and the predicted limits and natures of regular secondary structures (alpha or beta). Helices are treated as rigid cylinders, whereas beta-strands are collectively taken into account within beta-sheets modeled by helicoid surfaces. Strands are allowed to shift along their mean axis to allow some flexibility and the alpha-helices can be placed on either side of beta-sheets. Numerous initial conformations are produced by discrete rotations of the helices and sheets around the direction going from the center of their hydrophobic face to the global center of the protein. Selection of proposed models is based upon a criterion lying on the minimization of distances separating hydrophobic residues belonging to different regular secondary structures. The procedure is rapid and appears to be robust relative to the quality of starting data (nature and length of regular secondary structures). This dependence of the quality of the model on secondary structure prediction and in particular the beta-sheet topology, is one of the limits of the present algorithm. We present here some results for a set of 12 proteins (alpha, beta and alpha/beta classes) of lengths 40-166 amino acids. The r.m.s. deviations for core models with respect to the native proteins are in the range 1.4-3.7 A.

Algorithms↗

PubMed2002

Nonatomic solvent-driven Voronoi tessellation of proteins: an open tool to analyze protein folds.

A three-dimensional Voronoi tessellation of folded proteins is used to analyze geometrical and topological properties of a set of proteins. To each amino acid is associated a central point surrounded by a Voronoi cell. Voronoi cells describe the packing of the amino acids. Special attention is given to reproduction of the protein surface. Once the Voronoi cells are built, a lot of tools from geometrical analysis can be applied to investigate the protein structure; volume of cells, number of faces per cell, and number of sides per face are the usual signatures of the protein structure. A distinct difference between faces related to primary, secondary, and tertiary structures has been observed. Faces threaded by the main-chain have on average more than six edges, whereas those related to helical packing of the amino acid chain have less than five edges. The faces on the protein surface have on average five edges within 1% error. The average number of faces on the protein surface for a given type of amino acid brings a new point of view in the characterization of the exposition to the solvent and the classification of amino acid as hydrophilic or hydrophobic. It may be a convenient tool for model validation.

Algorithms↗