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Shedding light on cancer immunology at the molecular level: A quantum biochemistry study of representative PD-1/PD-L1
Victor L B França1, Jackson L Amaral2, Cláudia do Ó Pessoa3
1Department of Physiology and Pharmacology, Federal University of Ceará, 60430-270, Fortaleza, Ceará, Brazil; Department of Physics, Federal University of Ceará, Fortaleza, 60440-900, Brazil.
Background:
Programmed death 1 (PD-1) binding to PD-L1 is a potent mechanism used by immunogenic tumors to evade the immune system and the immune checkpoint PD-1PD-L1 has emerged as a promising target in the search for new drugs to improve cancer treatment. The crystallographic structure of humanPD-1humanPD-L1 shed light on the molecular characterization of this system and allowed computational studies to be carried out to characterize structural behaviors.
Methods:
This study demonstrated the importance of analyzing the flexibility of protein systems through molecular dynamics simulations (MDS) and its impacts on the interaction energy obtained through quantum biochemistry.
Results:
The computational results obtained provide a description of the flexibility and energetic profile of the PD-1PD-L1 contact surface using representative conformations from MDS. Variations of up to 50 % in the total interaction energy values were detected depending on the scrutinized conformation, which can be mainly attributed to the flexibility of the CC' loop, FG loop and ASP85-GLN91 of PD-1 and the MET58-LYS62 segment of PD-L1. Quantum biochemistry revealed the three hot spots in PD-L1: ARG113L-ARG125L > ILE54L-VAL76L > ALA18L-ASP26L; and two energetic hot spots in PD-1: ALA125-ARG139 > VAL63-GLN88. Nonetheless, VAL63-GLN88 and GLY124-ARG139 exhibit significant variation in interaction energy between different conformations, while ARG113L-ARG125L is the only hot spot with high energetic fluctuation on the PD-L1 surface.
Conclusion:
This is the first application of MDS coupled to dimensionality reduction and density functional theory (DFT) demonstrating new structural and energetic features that might be useful in discovering/designing more potent PD-1PD-L1 inhibitors.
Insights
Understanding protein flexibility is key for developing new cancer drugs targeting the PD-1/PD-L1 immune checkpoint. This study reveals how protein movement impacts drug interaction energy, aiding in the design of more effective cancer therapies.
Area of Science:
- Biochemistry
- Computational Biology
- Immunology
Background:
- The programmed death 1 (PD-1) and PD-L1 interaction is a critical mechanism tumors use to evade immune responses.
- Targeting the PD-1/PD-L1 immune checkpoint presents a promising strategy for novel cancer therapeutics.
Purpose of the Study:
- To investigate the impact of protein flexibility on the PD-1/PD-L1 interaction energy.
- To characterize the structural and energetic features of the PD-1/PD-L1 binding interface.
Main Methods:
- Molecular dynamics simulations (MDS) were employed to analyze protein system flexibility.
- Quantum biochemistry methods, including density functional theory (DFT), were used to calculate interaction energies.
- Dimensionality reduction techniques were coupled with MDS and DFT.
Main Results:
- Protein flexibility significantly influences PD-1/PD-L1 interaction energy, with variations up to 50% observed.
- Key flexible regions in PD-1 (CC' loop, FG loop, ASP85-GLN91) and PD-L1 (MET58-LYS62) were identified.
- Specific energetic hot spots in both PD-1 and PD-L1 were elucidated, with notable conformational variations in some hot spots.
Conclusions:
- This study is the first to combine MDS, dimensionality reduction, and DFT to analyze PD-1/PD-L1 interactions.
- The identified structural and energetic features offer valuable insights for designing more potent PD-1/PD-L1 inhibitors for cancer treatment.
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