Mapping the Binding Hot Spots on Human Programmed Cell Death 1 and Its Ligand with Free-Energy Simulations

The immune checkpoint
pathway of human programmed cell death 1
(hPD-1) and human programmed cell death ligand 1 (hPD-L1) is a promising
target for cancer treatment. The blockade of the interplay between
hPD-1 and hPD-L1 has recently shown good therapeutic efficacy. Although
crystallographic studies have provided static conformational snapshots
of the interface between hPD-1 and hPD-L1, the hot spot residues on
both proteins that play key roles in the association process still
remain elusive. To this end, we performed a series of alchemical free-energy
simulations to analyze the energetic contributions of the interfacial
residues on both hPD-1 and hPD-L1 and investigated the distributional
patterns of the residues that significantly contribute to the binding.
The results suggest that the hot spots on hPD-1 comprise Tyr68, Gln75,
Ile126, Leu128, Ile134, and Glu136, and the hot spots on hPD-L1 comprise LAsp26 (the L symbol refers to hPD-L1), LIle54, LTyr56, LMet115, LAsp122, LTyr123, and LLys124. Moreover, we found that the
distribution of these hot spot residues is highly uneven with respect
to either the energetic contribution or the side-chain polarity, with
energetically important residues clustered within densely packed hydrophobic
regions. The mechanism ruling the interaction of the two binding partners
is also discussed in detail from the perspective of the O-ring theory.
Our work provides clues for the future development of anticancer inhibitors
targeting the hPD-1/hPD-L1 immune checkpoint pathway.