The Too Many Faces of PD-L1: A Comprehensive Conformational Analysis Study

In the current study, we focused on the immune-checkpoints PD-1 pathway and in particular on the ligand PD-L1. We studied the conformational dynamics of PD-L1 through principal component analysis of existing crystal structures combined with classical and accelerated molecular dynamics simulations. We identified the maximum structural displacements that take place in all PD-L1 crystal structures and in the molecular dynamics trajectories. We found that these displacements are attributed to specific flexible regions in the protein. We also investigated the conformational preference for small molecule binding and highlighted a methionine residue at the binding site, which plays a key role in drug binding. The binding mechanism of PD-L1 to other binding partners is also discussed in detail from a computational perspective. We hope that the data presented here support the ongoing efforts to discover effective therapies targeting the PD-1 immune-checkpoint pathway.