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CDR backbone conformation -- contacts in three-dimensional space

The non-contacting residues within the CDRs coincide with residues identified by Chothia et al.chothia:HVRegions as important in defining canonical backbone conformations. Since, by definition, the side-chains of canonical key residues pack internally, they make few antigen contacts.

The variation in backbone conformations for the different canonicals is summarised in Figure 2.4. This highlights the broad conservation of different forms of CDR-L2, CDR-L3 and CDR-H2 and higher variability of CDR-L1, CDR-H1 and CDR-H3. In order to analyse the contacts made by the different CDR conformations, the mean fraction burial by antigen ( $\overline{\rho}$, see Section 2.2.2) is calculated for each CDR representative and is plotted in three dimensions in a `composite combining site' (Figure 2.4). This shows that, in general, only the central part of the combining site makes antigen contacts. The contact epicentre is displaced towards the heavy chain CDRs.

Figure 2.4: Antigen contacts and CDR conformation. Mean burial by antigen data ( $\overline{\rho}$) are shown on representatives of each different CDR conformation found in the complexed antibodies. Colours range from blue (zero mean burial) to red (high mean burial). CDR conformations shown in thick lines have six or more examples in the data set. Spacefilled carbon alpha atoms make at least one antigen contact. CDRs are fitted at framework atoms (see Methods).

Antigen contacts made by specific backbone conformations can be compared in CDR-L1 and CDR-H2, where there are sufficient numbers of different examples (6 or more). These two CDRs are shown in detail in Figure 2.5. Where CDR residues in two different canonical conformations are in the same position and orientation, the average contacts made are qualitatively similar. The insertion in CDR-L1 alters the sidechain orientations of residues L30 and L31 (Figures 2.5(a) and (b)) such that in the longer class 4 loop these never make contacts (in the shorter class 2 loop they do make contacts).

Figure 2.5: Comparing the antigen contacts made by different canonical loop conformations. (a) CDR-L1 canonical class 2 (7 examples) (b) CDR-L1 canonical class 4 (6 examples) (c) CDR-H2 canonical class 1 (6 examples) (d) CDR-H2 canonical class 2 (11 examples). Mean fractional burial by antigen ( $\overline{\rho}$) is shown (as a percentage) for each antigen contacting residue. Carbon alpha surface area is also proportional to $\overline{\rho}$.