Are frameworks independent from CDRs in antibodies? Exploring CDR-framework correlation networks of antibodies

The growing success of monoclonal antibodies (mAbs) in therapies highlights the importance of the humanization process in antibody design. This key step involves grafting selected complementarity-determining regions (CDRs) onto human frameworks (FWs) to reduce immunogenicity. However, the effect of this process on the antibody’s structure and dynamics is underexplored. This study uses molecular dynamics simulations to evaluate whether different CDRs can impact the framework of the antibody. Pertuzumab and Trastuzumab, two clinically approved antibodies, were selected for this evaluation because they differ only by their paratope. We performed molecular dynamic simulations of the Fab portion of both antibodies in antigen-bound and unbound conditions to analyze their interdomain mobility, orientation, interchain contacts and CDR-FW dynamical correlation networks. Our results show structural effects induced by distinct CDRs. Pertuzumab displayed greater domain mobility and distinct elbow angle distributions, particularly in the heavy chain. Additionally, interchain contacts differed between the antibodies, involving both CDR and FW residues. Cross-correlation analyses further revealed distinct CDR-FW communication networks, demonstrating long-range structural impacts of CDR residues on the elbow and constant domains. These findings underscore that CDRs significantly influence the antibody dynamics through CDR-FW correlation networks. This emphasizes the importance of considering these correlation networks in antibody design to enhance efficiency of the humanization process.