Guy Perez

Modeling of anti-nucleosome immunoglobulin Fv domains: analysis of electrostatic interactions.

Three-dimensional structural models of six murine anti-(H2A-H2B) monoclonal autoantibody variable fragments were built by comparative molecular modeling using the COMPOSER software. Analysis of the antibody combining sites is based on the hypothesis that ionic and/or electrostatic interactions predominate in antigen antibody binding, as suggested by the cationic nature of histones and the amino acid sequences of the antibody hypervariable regions. The study of the electrostatic potentials of their combining site surfaces, computed with the MOLCAD software, and the comparison with the electrostatic potentials of 13 selected control mAbs show the lack of a unique electrostatic pattern. One group of three mAbs expresses a strong and large electronegative area, supporting the hypothesis that ionic interactions predominate in antigen recognition. The second group, containing the other three mAbs, exhibits an alternation of electropositive and electronegative areas. All, however, present a localized electronegative area in the vicinity of H-CDR1 and H-CDR2 loops that is generated by the presence of at least one acidic residue. The model suggesting that the binding activity may depend on charged residues at the same site is reminiscent of what was previously reported in anti-DNA mAbs. In addition, the alternation of electropositive areas and electronegative areas in second group mAbs is also frequently observed in certain anti-DNA mAbs. These data argue for the existence of relationships between these two autoantibody populations and suggest that they share a common immunogenic particle formed by anionic and cationic components, such as a nucleosome.

Theoretical and Experimental Interpretation of the Signals From ΔITA

Discontinuous isoperibolic thermal analysis (ΔITA) is a phase diagram investigation technique applicable to organic components systems (with at least one liquid phase). The elementary signal is composed by the evolution of the temperature of the system vs. time after a composition shift. A theoretical analysis and a mathematical modeling of this signal show that the overall enthalpy exchanged multiplied by a proportional factor can be obtained. From different experiments, evidence is given that this semi-quantitative calorimetric measurement is reliable. Thus, ΔITA allows consistent and accurate descriptions of phase diagrams and is a real relative calorimetric measurement technique.

Structural models of antibody variable fragments: a method for investigating binding mechanisms.

The value of comparative molecular modeling for elucidating structure-function relationships was demonstrated by analyzing six anti-nucleosome autoantibody variable fragments. Structural models were built using the automated procedure developed in the COMPOSER software, subsequently minimized with the AMBER force field, and validated according to several standard geometric and chemical criteria. Canonical class assignment from Chothia and Lesks [Chottin and Lesk, J. Mol. Biol., 196 (1987) 901; Chothia et al., Nature, 342 (1989) 877] work was used as a supplementary validation tool for five of the six hypervariable loops. The analysis, based on the hypothesis that antigen binding could occur through electrostatic interactions, reveals a diversity of possible binding mechanisms of anti-nucleosome or anti-histone antibodies to their cognate antigen. These results lead us to postulate that anti-nucleosome autoantibodies could have different origins. Since both anti-DNA and anti-nculeosome autoantibodies are produced during the course of systemic lupus erythematosus, a non-organ specific autoimmune disease, a comparative structural and electrostatic analysis of the two populations of autoantibodies may constitute a way to elucidate their origin and the role of the antigen in tolerance breakdown. The present study illustrates some interests, advantages and limits of a methodology based on the use of comparative modeling and analysis of molecular surface properties.

Influence of water molecules on the nucleation rate of polymorphic complexes with different conformations in solution

The structural resolution of several hydrated copper(II) sulfoxinates (hereafter [CuSu(H2O)2].kH2O, k=0, 1, 2) has shown that, in the solid state, molecules exist as dimerunits [CuSu(H2O)2]2 (figure 1) with different conformations (1–3). In order to understand the relationship between the conformation in solids and the nucleation rates, we have modelized the conformation of the solvated complexes in aqueous solution at 20°C.

Influence de l'addition de cuivre sur les proprietes structurales et physiques de VO2

Abstract Magnetic susceptibility, DTA, X-ray diffraction and EPR of Cu x V 1−x O 2 samples have been studied. A new Q-phase stable at low temperature is reported. Analogies with M III x V 1−x O 2 phases (M III = Al, Cr, Fe) are discussed.