Antibody maturation increases rigidity in protein-contacting regions and flexibility at glycan interfaces

Abstract

Antibody design is a challenging task that could be improved by understanding the conformational changes accompanying affinity maturation. Antibody maturation is a critical immune system process by which antibodies gain mutations that improve affinity and specificity for antigen targets. However, how these mutations change antibody dynamics, specifically whether antibodies become more rigid as they mature, remains a contested topic. Using adaptive sampling molecular dynamics simulations and over 8.5 milliseconds of Folding@home simulations of seven lineages, we discover that affinity maturation selectively tunes the dynamics of antibody paratope regions depending on whether they contact protein residues or glycans. We find that antibody regions that contact glycans evolve to become more flexible and, consistent with other studies, antibody regions that contact protein residues on the antigen become rigid. This pattern holds regardless of whether one includes the constant region in the simulations, indicating that the computational cost of all-atom antibody MD simulations can be reduced by half without sacrificing the accuracy of the variable regions dynamics. We expect the principles identified in this study will enable precise, dynamics-based engineering of high-affinity antibodies and to inform immunogen design against challenging, glycan-shielded viral targets such as HIV. Significance StatementAntibodies are currently one of the most powerful therapeutics available. Our bodies evolve antibodies to bind a target (called an antigen) through a process called maturation. Understanding how antibody dynamics change during maturation would lead to improved antibody design strategies. Through extensive all-atom molecular dynamics simulations of multiple antibody lineages, we demonstrate that the dynamics accompanying affinity maturation are dependent on the antigen binding site. Antibody regions that contact protein residues on the antigen become rigid while regions that contact glycans gain flexibility with maturation. These findings can be leveraged for improved, dynamics-based antibody design.