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

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

doi:10.1038/s41598-019-53216-z

Hocheol Lim, Jongwan Kim + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-53216-z

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Journal: Scientific Reports	Publication Date: Nov 13, 2019
Citations: 46	License type: open-access

Affiliation: Yonsei University

Abstract

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.

Highlights

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
quantum mechanics (QM) could not be applied to the large biological systems, such as PPI, due to huge computational cost[15], it provides the analysis of the components of molecular interaction in post Hartree-Fock level with energy decomposition analysis (EDA) method, developed by Morokuma et al.[16]
Analyzing protein-protein interactions (PPI) between a target protein and a partner protein can be correlated with analyzing pair interaction energy (PIE) in fragment molecular orbital (FMO) calculations with a-fragment-per-a-residue fragmentation scheme

Summary

Introduction

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. QM could not be applied to the large biological systems, such as PPI, due to huge computational cost[15], it provides the analysis of the components of molecular interaction in post Hartree-Fock level with energy decomposition analysis (EDA) method, developed by Morokuma et al.[16]. As a practical application of EDA, Kitaura et al developed fragment molecular orbital (FMO) method for large molecules and molecular systems in 199917, and pair interaction energy decomposition analysis (PIEDA) in 200718. It has advantages of drastically reducing the computing time without compromising the accuracy of the results compared with traditional QM method, and of providing PIEDA as a practical application of EDA. In case of PPI as a large molecular system, there have been a few cases to apply FMO method, where a partner protein was defined as a fragment for facilitating PPI analysis and it required huge computational cost[23]

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