Abstract
Antibodies, through their ability to target virtually any epitope, play a key role in driving the adaptive immune response in jawed vertebrates. The binding domains of standard antibodies are their variable light (V(L)) and heavy (V(H)) domains, both of which present analogous complementarity-determining region (CDR) loops. It has long been known that the V(H) CDRs contribute more heavily to the antigen-binding surface (paratope), with the CDR-H3 loop providing a major modality for the generation of diverse paratopes. Here, we provide evidence for an additional role of the V(L) domain as a modulator of CDR-H3 structure, using a diverse set of antibody crystal structures and a large set of molecular dynamics simulations. We show that specific attributes of the V(L) domain such as subtypes, CDR canonical forms and genes can influence the structural diversity of the CDR-H3 loop, and provide a physical model for how this effect occurs through inter-loop contacts and packing of CDRs against each other. Our results indicate that the rigid minor loops fine-tune the structure of CDR-H3, thereby contributing to the generation of surfaces complementary to the vast number of possible epitope topologies, and provide insights into the interdependent nature of CDR conformations, an understanding of which is important for the rational antibody design process.