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Not one of the residues in the combining site is in contact with antigen in all the structures (black bars in Figures 2.1 & 2.2). On average, potential antigen contacting residues form contacts in only 7.4 out of a possible 26 structures (28%) although at least one residue from each CDR forms contacts in 18 or more structures except in CDR-L2 which, as reported elsewhere[Wilson & Stanfield, 1993,Wilson & Stanfield, 1994], only rarely contributes to antigen binding. Residues from CDR-L3 dominate; L91, L94 and L96 each make contacts to 21 different antigens. CDR-H3 is also dominant, but its length variability makes it impossible to assign special significance to particular residues.
In agreement with Padlan's survey of 22 complexes[Padlan et al., 1995], the data show that for CDR-H1 and CDR-H2, where the loop and variability definitions differ, the common contacting residues correspond better with Kabat's sequence variability definition (Figures 2.2(a) and (b), dashed arrows). In view of the data, however, we propose a new CDR definition based on observed antigen contacts (Table 2.3 column 4, see Table footnote for definition). In two cases (CDR-L1 and CDR-H2) the Kabat CDR definitions contain a large number of mostly non-contacting residues (L24 to L29 and H59 to H65 respectively) which can be explained simply by the gross arrangement of the CDRs with respect to the centre of the combining site, where most antigen interactions occur (Figure 2.3). A number of residues outside the standard CDR definitions make antigen contacts (number in parentheses): L36 (1), L46 (2), L49 (6), H30 (5), H47 (4) and H93 (1). The residues making fewer contacts (L36, L46, H47 and H93) generally have less solvent accessibility (grey bars in Figures 2.1 & 2.2) and are often buried by other antibody residues. Because these residues are located in the centre of the combining site, they tend to make antigen contacts when they are exposed to solvent (CDR residues L34, L89, H35 and H50 also behave in this way).
Within each CDR (CDR-L3 and CDR-H3 in particular), more contacts are made at the end of the loop closer to the centre of the combining site, whilst apical loop residues interact less often with antigen.