computer modeling in molecular biology.pdf

26 Tim .l I! Hubbard and Arthur M. Leskchanges at a few specific sets of positions switch the main chain to a differentcanonical conformation.As an example Figure 2-7 shows the L3 loop from VK McPC603. In this, the mostcommon VK L3 conformation, there is a proline at position 95 in the loop, in a cisconformation. Hydrogen bonds between the side chain of the residue at position 90,just N-terminal to the loop, and the main chain atoms of residues in the loop,stabilise the conformation. The side chain is an Asn in McPC603; it can also be aGln or His in other VK chains. The combination of the polar side chain at position90 and the proline at position 95 constitute the “signature” of this conformation inthis loop, from which it can be recognised in a sequence of an immunoglobulin ofunknown structure.bFigure 2-7. An antigen-binding loop from the VK domain of the immunoglobulin McPC603.This loop contains a cis-proline, and is stabilised by hydrogen bonding between a polar sidechain just N-terminal to the loop and inward-pointing main chain atoms in the loop.bThe observed conformations are determined by the interactions of a few residuesat specific sites in the hypervariable regions and, for certain loops, in the frameworkregions. Hypervariable regions that have the same conformations in different immunoglobulinshave the same or very similar residues at these sites. On the basis ofthe canonical structural model, it has been possible to create a detailed roster of thecanonical conformations of each loop - with the possible exception of H3 whichis more complicated and still uncertain - and the sets of “signature” residues thatpermit discrimination among them.A procedure to predict the structures of the variable domains of immunoglobulinshas been formulated based on the structures of solved immunoglobulins and thecanonical structure model of the conformations of the hypervariable loops [65].