Kinetics of pH-dependent interactions between PD-1 and PD-L1 immune checkpoint proteins from molecular dynamics

Area of Science:

• Immunology
• Computational Biology
• Biochemistry

Background:

• Immune checkpoint inhibitors targeting PD-1/PD-L1 pathways offer promising cancer immunotherapy.
• Tumor microenvironments exhibit acidic pH (5.5-7.0), influencing protein-ligand interactions.
• Exploiting pH-dependent binding could enhance drug specificity and efficacy in cancer treatment.

Purpose of the Study:

• To investigate the mechanism and kinetics of pH-dependent binding and unbinding for the PD-1/PD-L1 complex.
• To explore how physiological (pH 7.4) and tumor (pH 5.5) pH conditions affect PD-1/PD-L1 interactions.
• To identify molecular determinants of pH-dependent affinity modulation.

Main Methods:

• Classical molecular dynamics simulations were employed.
• Simulations were conducted at two distinct pH levels: 7.4 (physiological) and 5.5 (acidic tumor microenvironment).
• Analysis focused on binding/unbinding kinetics and key residue protonation states.

Main Results:

• A significant increase in PD-1/PD-L1 binding affinity was observed at lower pH (5.5) compared to physiological pH (7.4).
• The protonation state of Histidine 68 (His68) in PD-1 was identified as critical for stabilizing the complex at acidic pH.
• Calculated reaction rate constants showed qualitative agreement with experimental data.

Conclusions:

• pH is a critical regulator of PD-1/PD-L1 interactions, with acidic tumor environments substantially increasing binding affinity.
• Molecular insights into pH-dependent binding, particularly the role of His68, can guide the rational design of improved immune checkpoint inhibitors.
• This study provides a foundation for engineering binding and unbinding kinetics for more potent cancer immunotherapies.