Effect of Fragment 1 on the Binding of Epigallocatechin Gallate to the PD-L1 Dimer Explored by Molecular Dynamics

Author:

Guo Yan1,Guo Yilin1,Guo Zichao1,Liu Boping2,Xu Jianguo1

Affiliation:

1. College of Food Science, Shanxi Normal University, Taiyuan 030031, China

2. Key Laboratory for Bio-Based Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510630, China

Abstract

Blocking the interaction between programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) by directly targeting the PD-L1 dimer has emerged as a hot topic in the field of cancer immunotherapy. Epigallocatechin gallate (EGCG), a natural product, has been demonstrated binding to the PD-L1 dimer in our previous study, but has a weaker binding capacity, moreover, EGCG is located at the end of the binding pocket of the PD-L1 dimer. The inhibitor fragment 1 (FRA) lies at the other end. So, we proposed that the introduction of FRA might be able to improve the binding ability. To illuminate this issue, molecular dynamics (MD) simulation was performed in the present study. Binding free energy calculations show that the binding affinity is significantly increased by 17 kcal/mol upon the introduction of FRA. It may be due to the energy contributions of emerging key residues ATyr56, AMet115, BTyr123, AIle54 and the enhanced contributions of initial key residues ATyr123 and BVal68. Binding mode and non-bonded interaction results indicate that FRA_EGCG (EGCG in combination with FRA) binds to the C-, F- and G-sheet of the PD-L1 dimer. Importantly, the introduction of FRA mainly strengthened the nonpolar interactions. The free energy landscape and secondary structure results further show that FRA_EGCG can interact with the PD-L1 dimer more stably. These data demonstrated here provide the theoretical basis for screening two or more natural products with additive inhibitory effect on this pathway and therefore exerting more effective anticancer immunity.

Funder

Research Start-up Funds for the High-level Talent Introduction Project of South China Agricultural University

Fundamental Research Program Project of Shanxi Province

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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