RETHINKING SHAPE SPACE - EVIDENCE FROM SIMULATED DOCKING SUGGESTS THAT STERIC SHAPE COMPLEMENTARITY IS NOT LIMITING FOR ANTIBODY-ANTIGEN RECOGNITION AND IDIOTYPIC INTERACTIONS

The concept of ''shape space'' is based on the assumption that the rel evant properties of individual molecules can be adequately specified b y a finite list of N parameters; and that c(ij), the affinity between molecules i and j, can be specified by an equation of the form: c(ij) = f(x(i),x(j)), where (x)i and x(j) are N-dimensional vectors represen ting the absolute positions of molecules i and j in an objective, refe rential ''shape space'', and f is an appropriate function. We have per formed simulated docking of the combining sites of immunoglobulin mole cules, based on their crystallographic structures. The results suggest that shape complementarity cannot account for the specificity of idio typic interactions, since in the simulations each pair of docked prote ins had a buried surface area as great as that occurring in known comp lexes. It therefore seems likely that the atomic interactions accounti ng for the specificity of immunoglobulin recognition are highly relati onal. This casts doubt on the basic assumptions underlying the shape-s pace concept, at least in the simple form hitherto used in theoretical modelling of the immune system. In order to be realistic, the dimensi onality N would have to be high (more than 20), and the function f wou ld be irregular and discontinuous. Alternatively, if the equation c(ij ) = f(x(i),x(j)) is interpreted as a purely formal construction in an abstract ''inversion space'', its validity is entirely relative to the empirical affinity matrix on which the construction is based. We conc lude that at present there is no sure way of adequately characterizing the internal structure of idiotypic affinity matrices; and that model s of the immune system should therefore aim at being generic and robus t with respect to the structure of the idiotypic affinity matrices of unselected immunoglobulins.