Molecular dynamics simulations elucidate conformational selection and induced fit mechanisms in the binding of PD-1...

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1) and its ligand PD-L1 pathway have shown significant promise in cancer therapy.
• Structural studies of PD-1 reveal conformational flexibility, particularly in the CC' loop, which transitions between open and closed states.

Purpose of the Study:

• To investigate the role of the CC' loop's conformational dynamics in the molecular recognition between PD-1 and PD-L1.
• To elucidate the binding mechanism by comparing apo-PD-1 and the PD-1/PD-L1 complex.

Main Methods:

• Molecular dynamics simulations were employed to compare the open and closed conformations of the CC' loop in apo-PD-1 and the PD-1/PD-L1 complex.
• Analysis focused on hydrogen bonding patterns and conformational transitions.

Main Results:

• The CC' loop in apo-PD-1 can access both open and closed states due to the moderate stability of intramolecular hydrogen bonds (SER71-THR120).
• PD-L1 binding promotes a rapid switch to the closed conformation and stabilizes it via four new intermolecular hydrogen bonds.
• This suggests a binding mechanism involving both conformational selection and induced fit.

Conclusions:

• The conformational flexibility of the PD-1 CC' loop is a critical determinant in its interaction with PD-L1.
• Understanding this dynamic interplay is crucial for the rational design of novel structure-based drugs targeting the PD-1/PD-L1 axis for cancer immunotherapy.