Residue Specific Binding Mechanisms of PD-1 to Its Monoclonal Antibodies by Computational Alanine Scanning

Molecular dynamics simulations were conducted on two PD-1/monoclonal antibody ( pembrolizumab , nivolumab) complexes separately. The binding hotspots of the monoclonal antibody (mAb) and PD-1 were predicted by using efficient computational alanine scanning method. The comparation between the predicted hotspots and the important residues in PD-1/PD-L1 complex shows that pembrolizumab combines with PD-1 in a way similar to PD-L1, while nivolumab combines with PD-1 in a more different way by N-loop. (PD-1)K131 is the only hotspot shared by the two PD-1/mAb complexes. It is also found that key residues of mAbs binding to (D-1)K131 are similarly dominated by van der Waals (vdW) energy. Furthermore, hotspots on both the monoclonal antibodies are dominated by vdW energy, indicating a demand to improve the contributions of electrostatic energy. The present work provides important insights for the design of new mAbs targeting PD-1.

Automated summary

Molecular dynamics simulations were conducted on two PD-1/monoclonal antibody complexes, pembrolizumab and nivolumab, revealing different binding mechanisms. Both complexes share (PD-1)K131 as a binding hotspot, dominated by van der Waals energy. Improving the contributions of electrostatic energy may enhance the efficiency of monoclonal antibodies binding to PD-1.