The blockade of immune checkpoints, such as programmed
death receptor 1 (PD-1) and
programmed death ligand 1 protein (PD-L1), is a promising therapeutic approach in
cancer immunotherapy.
Nivolumab, a humanized
IgG4 antibody targeting PD-1, was approved by the US Food and Drug Administration for several
cancers in 2014. Crystal structures of the
nivolumab/PD-1 complex show that the
epitope of PD-1 locates at the IgV domain (including the FG and BC loops) and the N-terminal loop. Although the N-terminal loop of PD-1 has been shown to play a dominant role in the complex interface of the static structure, its role in the dynamic binding process has not been illustrated clearly. Here, eight molecular systems were established for
nivolumab/PD-1 complex, and long-time molecular dynamics simulations were performed for each. Results showed that the N-terminal loop of PD-1 prefers to bind with
nivolumab to stabilize the interface between IgV and
nivolumab. Furthermore, the binding of the N-terminal loop with
nivolumab induces the rebinding between the IgV domain and
nivolumab. Thus, we proposed a two-step binding model for the
nivolumab/PD-1 binding, where the interface switches to a high-affinity state with the help of the N-terminal loop. This finding suggests that the N-terminal loop of PD-1 might be a potential target for anti-PD-1 antibody design, which could serve as an important gatekeeper for the anti-PD-1 antibody binding.