Identifying the Key Residues Regulating the Binding between Antibody Avelumab and PD-L1 VIA Molecular Dynamics Simulation

Avelumab, approved by the US Food and Drug Administration (FDA) for the treatment of Merkel cell carcinoma in adults and paediatric patients in 2017, is an investigational fully human anti–PD-L1 IgG1 antibody that inhibits PD-1/PD-L1 interactions. Although the crystal structure of the avelumab/PD-L1 complex was reported in 2017, which provided us the interface information at atom level, the dynamics information of the complex is missed, and some key residues could not be detected in that static crystal structure. Here, molecular dynamics simulations were performed for the avelumab/PD-L1 complex to map the epitope to paratope residues. The results showed that the epitope residues locating on the C strand (PD-L1TYR56 and PD-L1GLU58), CC’ loop (PD-L1GLU60, PD-L1ASP61 and PD-L1LYS62), C’ strand (PD-L1ASN63), and C'D loop (PD-L1HIS69) of PD-L1 mainly form the interface with avelumab. The paratope residues on avelumab include TYR52H, SER54H, GLY102H, THR105H, TYR34L, ASP52L and ARG99L. The C’ strand of PD-L1 is also a binding region for PD-1. Thus, antibody avelumab block PD-1/PD-L1 interaction through direct competitive binding of the C’ strand of PD-L1.