Internal motions of antibody molecules

Abstract

ANTIBODY molecules of the IgG class are composed of three covalently linked regions^1,2. Two of these (designated Fab) are identical and bind antigen; the third (Fc) has been identified as the site of antibody effector functions (for example, complement fixation), which are activated by antigen binding³. There is evidence that the binding of antigen to the Fab region induces an allosteric transition in IgG and that this transition may be a step in the effector activation process⁴. The findings of Pecht et al.⁵ indicate that for complement fixation both Fab regions must bind antigen, even though binding to one induces some conformational change in Fc. Binding of hapten does not lead to complement fixation in general, but some exceptions to this rule are known⁶. The interchain disulphide bridges must be intact for Fab ligand binding to have a productive effect on the Fc region^7,8. Both the Fab and Fc regions have a domain structure; each consists of a pair of compact lobes covalently linked by strands of polypeptide chains⁹. A schematic diagram of the connectivity of the IgG lobes is given by Padlan¹⁰. One of the fundamental questions involved in antibody function is the nature of the mechanism by which binding of antigen to the Fab regions affects the Fc region. Huber et al. have recently outlined a possible allosteric model for the activation step on the basis of X-ray and other data⁹. In this note we use simple diffusion arguments to estimate the characteristic times associated with the Huber proposal. Since the analysis deals only with the relative motion of the IgG domains, it is possible that slower intradomain structural changes are also involved in the activation process; if so, the estimated characteristic times would be lower bounds for the activation time. The role of conformational transitions in effector function activation is still in dispute¹¹, but we note that the diffusional model may be useful for analysing other dynamical phenomena in immunoglobulins, such as their fluorescence depolarisation behaviour^12–14.