Klaus R. Liedl, PhD, Professor & Head, General, Inorganic & Theoretical Chemistry, University of Innsbruck
In contrast to the prevalent static view of the binding interface, we demonstrate a dynamic perspective not only of the paratope, but of whole Fvs and Fabs. We show that antibodies exist as ensembles of paratope states. These paratope states are defined by a characteristic combination of CDR loop conformations and interdomain orientations. They interconvert into each other in the micro-to-millisecond timescale by correlated loop and interdomain rearrangements. We demonstrate that crystal packing effects can distort the paratope state and thus, result in misleading X-ray structures. By advancing the repertoire of cutting-edge simulation techniques, for the first time we achieve a complete description of conformations, thermodynamics, and kinetics of the whole binding paratope in solution. These findings have broad implications in the field of antibody design and in the development of biotherapeutics, as they provide a new paradigm in the understanding of CDR-binding loop states, antibody-antigen recognition, relative VH and VL interface angles, and elbow-angle distributions and their respective dynamics. Preliminary findings are already published in six manuscripts, but a considerable number of further publications is upcoming. These upcoming publications will also address issues like inter-loop correlation and the relationship of Fv-interface dynamics with loop rearrangements.