Abstract A98: Molecular dynamics study of pH-dependent interactions between immune checkpoint receptor PD-1 and PD-L1

Abstract

Abstract Understanding of how small variations in checkpoint protein chemistry (e.g., mutations) and tumor immune microenvironment (e.g., pH) influence receptor-ligand binding and define both the mechanisms and magnitude of immune response is of great importance, but the molecular details are still missing. Here, we employ enhanced free-energy sampling molecular dynamics simulations to unveil pH-dependent binding/unbinding mechanisms and kinetics of PD-1/PD-L1 interactions. By identifying the binding pocket in the PD-1/PD-L1 complex, we show a key role of the His68 protonation state in PD-1 in the complex stabilization at low pH. Specifically, we estimate the unbinding free-energy barrier to be around 15 kJ/mol higher at pH 5.5 than at pH 7.4. The estimated ratio of binding (kon) and unbinding (koff) rate constants is found to agree well with recent experimental data on KD values at different pH. Also, simulations show an important role of solvation state of the binding pocket in mediating polar interactions at the PD-1/PD-L1 binding interface. These initial molecular insights are important for further engineering of binding/unbinding kinetics to formulate more efficient immune checkpoint blockade strategies. Citation Format: Vitaly Alexandrov, Konstantin Klyukin. Molecular dynamics study of pH-dependent interactions between immune checkpoint receptor PD-1 and PD-L1 [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A98.