Investigation of protein-protein interactions and hot spot region between PD-1 and PD-L1 by fragment molecular orbital method

Hocheol Lim, Jungho Chun, Xuemei Jin, Jongwan Kim, Jeong Hyeok Yoon, Kyoung Tai No

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32 Citations (Scopus)


Inhibitors to interfere protein-protein interactions (PPI) between programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) block evasion of cancers from immune surveillance. Analyzing hot spot residues in PPI is important for small-molecule drug development. In order to find out hot spots on PPI interface in PD-1/PD-L1 complex, we analyzed PPI in PD-1/PD-L1 with a new analysis method, 3-dimensional scattered pair interactions energies (3D-SPIEs), which assorts significant interactions with fragment molecular orbital (FMO) method. By additionally analyzing PPI in PD-1/antibody and PD-L1/antibody complexes, and small-ligand interactions in PD-L1/peptide and PD-L1/small-molecule complexes, we narrowed down the hot spot region with 3D-SPIEs-based interaction map, which integrates PPI and small-ligand interactions. Based on the map, there are two hot spot regions in PPI of PD-1/PD-L1 and the first hot spot region is important for inhibitors. In particular, LY56, LE58, and LN66 in the first hot spot of PD-L1 are important for PD-L1-antibodies and small-inhibitors in common, while LM115 is important for small-inhibitors. Therefore, the 3D-SPIEs-based map would provide valuable information for designing new small-molecule inhibitors to inhibit PPI of PD-1/PD-L1 and the FMO/3D-SPIEs method provides an effectual tool to understand PPI and integrate PPI and small-ligand interactions at a quantum mechanical level.

Original languageEnglish
Article number16727
JournalScientific reports
Issue number1
Publication statusPublished - 2019 Dec 1

Bibliographical note

Funding Information:
This work was supported by the Brain Korea 21 (BK21) PLUS program and the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2018M3A9G2062552).

Publisher Copyright:
© 2019, The Author(s).

All Science Journal Classification (ASJC) codes

  • General


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