Antibody/Antigen Picture

Catalytic antibodies are able to bind their antigen and to perform chemical reaction such as esterification or hydrolysis of the hapten. High resolution crystal structures of an esterolytic antibody, obtained by Wedemayer et al, provide insights on the structure of the antibody both before and after the refinment of its catalytic activity. Analysis of the crystal structures suggests that the mature antibody, wich differs from the germline antibody by 9 mutations, is preadapted for the aquisition of catalytic function. Whereas fixation of the hapten on the germline antibody leads to significant structural rearangments, the unbond state of the matured antibody is closer to its bond state. These experimental results suggest that the mature form of the antibody has probably a more rigid structure than the germline form. The germline would have more conformational flexibility, and therefore a slower binding rate, as it has to "search" space for its best fitting structure with the antigen.

Our plans to test this hypothesis are:

  1. Semi-empirical calculations to parametrize the hapten.
  2. Build four systems: wild-type; wild-type + hapten; mutant; mutant + hapten. Hydrate and equilibrate the systems.
  3. Run MD simulations of the four systems and check possible diferrences in terms of large-scale conformational changes, using PCA tools.
  4. Use SMD to unbind the hapten and check the differences in unbinding for the wild-type and mutant structures.
  5. Use Bioinformatics to suggest possible mutation paths for maturation.