Deciphering PD1 activation mechanism from molecular docking and molecular dynamic simulations

The activation of T cells is normally accompanied by inhibitory mechanisms within which the PD1 receptor stands out. Upon binding the ligands PDL1 and PDL2, PD1 drives T cells to an unresponsive state called exhaustion characterized by a markedly decreased capacity to exert effector functions. For this reason, PD1 has become one of the most important targets in cancer immunotherapy. Despite the numerous studies about PD1 signaling modulation, how the PD1 signaling is activated upon the ligands’ binding remains an open question. Several experimental facts suggest that the activation of the PD1-PLD1 pathway depends on the interaction with an unknown partner at the cellular membrane. In this work, we investigate the possibility that the target of PD1-PDL1 is the same PD1-PDL1 complex. We combined molecular docking to explore different binding modes with molecular dynamics and umbrella sampling simulations to assess the complexes’ stability. We found a high molecular weight complex that explains the activation of PD1 upon PDL1 binding. This complex has an affinity comparable to the PD1-PDL1 interaction and resembles the form of a linear lattice.