Maturation of an antibody response is governed by modulations in flexibility of the antigen-combining site

Although affinity maturation constitutes an integral part of T-dependent hu moral responses, its structural basis is less well understood. We compared the physicochemical properties of antigen binding of several independent an tibody panels derived from both germline and secondary responses. We found that antibody maturation essentially reflects modulations in entropy-contro l of the association, but not dissociation, step of the binding. This influ ence stems from variations in conformational heterogeneity of the antigen-c ombining site, which in turn regulates both the affinity and specificity fo r antigen. Thus, the simple device of manipulating conformational flexibili ty of paratope provides a mechanism wherein the transition from a degenerat e recognition capability to a high-fidelity effector response is readily ac hieved, with the minimum of somatic mutations.