When theory meets experiment: the PD-1 challenge.

Applying atomistic computational modeling to drug discovery has proven to be a hugely successful approach, allowing drug-receptor interactions to be predicted and drugs to be optimized for potency, selectivity, and safety. However, when it comes to predicting protein-protein interactions and to rationally designing regulators of these interactions, computational tools often fail. Here, we report one of the rare instances where state-of-the-art computer simulations, guided by experiment, were able to correctly predict one of the most sophisticated protein-protein interactions. We revisit our previous discovery of the complex of human PD-1 with the ligand PD-L1 and compare our earlier findings with the recently published crystal structure of the same complex. Side-by-side comparison of the model of the complex with its crystal structure reveals outstanding agreement and suggests that our protein-protein prediction workflow could be applied to similar problems.