Specific Interactions of Protein-Protein Interaction between Human Programmed Death 1 (PD-1) and its Ligand 1 (PD-L1) with AB Initio Fragment Molecular Orbital Method

Abstract

Immunologic checkpoint pathways, including Programmed Death 1 and its ligands, are crucial in mediating self-tolerance and preventing autoimmunity, so they protect tissues from self-damage. It is now clear that significant numbers of cancers manipulate the signal pathways to evade immune surveillance and efficacy of the blockade of immune checkpoints in cancer therapy was validated in preclinical studies targeting programmed death 1. Several therapies, including small molecules, to interfere interactions between PD-1 and PD-L1 have been developed. Nevertheless, this is obstructed by the imperfect structure information about these proteins, even after the crystal structures were solved. Here, we applied ab initio fragment molecular orbital method to wild-type PD-1/PD-L1 complex at MP2/6-31G∗ level with PCM. Furthermore, we also applied the FMO method to two complexes of small molecule inhibitors targeting PD-L1 at MP2/6-31G∗∗ level with PCM. Based on calculated pair interaction energies (PIEs), we revealed key interactions and quantified the strength of the interactions with Pair Interaction Energy Decomposition Analysis (PIEDA) and a visual representation of 3D scatter plot of PIEs, a so-called 3D SOP. As a result, we investigated specific interactions in previously reported three hot spots on a basis of the FMO results. This approach provides an effectual tool to understand the protein-protein interactions at the quantum mechanical level.