The structures of over 30 Fab fragments have been solved using X-ray diffraction methods. The available coordinates are being used to model the variable region of other immunoglobulins for which only the sequence is known. Modeling the combining site of an immunoglobulin is a much more difficult problem than is usually perceived. The method described here, although computationally intensive, has the potential to provide reasonable models in many cases. After the best parent molecule is selected, all residues that can be affected by the sequence changes are identified and all their possible conformations analyzed. Methods for reducing the computational complexity of the procedure are proposed. If a parent molecule that has high degree of homology with the one being modeled is identified the method provides a way of exhaustively analyzing all conformations that could include the correct final structure. In these cases the final model will be quite similar to the correct structure. However, even in favorable cases, neither this nor other methods can provide a model that is accurate enough for understanding phenomena that depend critically on the accuracy of the coordinates.
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