Paratope states in solution improve structure prediction and docking

Structure-based antibody design and accurate predictions of antibody-antigen interactions remain major challenges in computational biology. By using molecular dynamics simulations, we show that a single static X-ray structure is not sufficient to identify determinants of antibody-antigen recognition. Here, we investigate antibodies that undergo substantial conformational changes upon antigen binding and have been classified as difficult cases in an extensive benchmark for antibody-antigen docking. We present thermodynamics and transition kinetics of these conformational rearrangements and show that paratope states can be used to improve antibody-antigen docking. By using the unbound antibody X-ray structure as starting structure for molecular dynamics simulations, we retain a binding competent conformation substantially different to the unbound antibody X-ray structure. We also observe that the kinetically dominant antibody paratope conformations are chosen by the bound antigen conformation with the highest probability. Thus, we show that paratope states in solution can improve antibody-antigen docking and structure prediction.

Automated summary

Structure-based antibody design and accurate predictions of antibody-antigen interactions are challenging tasks in computational biology. Molecular dynamics simulations reveal that a single static X-ray structure is insufficient to understand the determinants of antibody-antigen recognition. This study investigates antibodies that undergo significant conformational changes upon antigen binding and demonstrates that the paratope states can be utilized to enhance antibody-antigen docking.