Structure of antibody hypervariable loops reproduced by a conformational search algorithm

The antigen-combining site of antibody molecules consists of six separate loops supported by a conserved β-sheet framework; antibody specificity arises from length and sequence variation of these 'hypervariable' loops1 and can be manipulated by transferring sets of loops between different frameworks2. Irregular loops are the most difficult parts of protein structure to understand and to model correctly3–6. Here, we describe two computer experiments where all the hypervariable loops were deleted from X-ray structures of mouse immunoglobulins and reconstructed using the conformational search program CONGEN7. A protocol was developed for reconstruction of the hypervariable loops in McPC 603 antibody. Calculated loop conformations were generated and a model of the combining site was built from selected low-energy conformations. We then modelled hypervariable loops in another antibody molecule, HyHEL-5. Both models agreed well with the known crystal structures. Our results hold out promise for the success of future modelling studies of complete antigen-combining sites from amino acid sequences.