A scenario-based approach to modeling development: a prototype model of C. elegans vulval fate specification.

Studies of developmental biology are often facilitated by diagram "models" that summarize the current understanding of underlying mechanisms. The increasing complexity of our understanding of development necessitates computational models that can extend these representations to include their dynamic behavior. Here we present a prototype model of Caenorhabditis elegans vulval precursor cell fate specification that represents many processes crucial for this developmental event but that are hard to integrate using other modeling methodologies. We demonstrate the integrative capabilities of our methodology by comprehensively incorporating the contents of three seminal papers, showing that this methodology can lead to comprehensive models of developmental biology. The prototype computational model was built and is run using a language (Live Sequence Charts) and tool (the Play-Engine) that facilitate the same conceptual processes biologists use to construct and probe diagram-type models. We demonstrate that this modeling approach permits rigorous tests of mutual consistency between experimental data and mechanistic hypotheses and can identify specific conflicting results, providing a useful approach to probe developmental systems.

Monoclonal antibody to a DNA-binding domain of p53 mimics charge structure of DNA: anti-idiotypes to the anti-p53 antibody are anti-DNA.

Antibodies to DNA are important markers of various autoimmune diseases and can be pathogenic; however, their generation is not understood. We previously reported that anti-DNA antibodies could be induced in mice by idiotypic immunization to PAb-421, an antibody to a DNA-binding domain of p53. We now report that two monoclonal antibodies of moderate affinity (K(D) asymptotically equal to 10(-7)), raised from PAb-421-immunized mice, specifically recognized both PAb-421 and DNA. These antibodies feature multiple arginine residues in the antigen-binding site, a unique characteristic of disease-associated anti-DNA antibodies; nevertheless, these anti-DNA antibodies show specific complementarity to PAb-421 by competing with p53 for PAb-421 binding and recognize defined oligonucleotides with a specificity similar to that of p53. To study the structural basis for the cross-recognition of PAb-421 and DNA by the anti-DNA antibodies, we constructed computer models (fine-tuned by protein-protein docking) of PAb-421 and one of the monoclonal anti-DNA antibodies. The modeled structures manifested structural complementarity. Most notably, the modeled structure of PAb-421 resembled the structure of DNA by the positions of negatively charged groups and aromatic side chains. Thus, a protein molecule may mimic the structure of DNA and the elusive generation of anti-DNA antibodies could be explained by idiotypic immunity to a DNA-binding protein, like p53.