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Kinetics of pH‐dependent interactions between PD‐1 and PD‐L1 immune checkpoint proteins from molecular dynamics
Author(s) -
Klyukin Konstantin,
Alexandrov Vitaly
Publication year - 2020
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.25885
Subject(s) - immune checkpoint , kinetics , chemistry , protonation , receptor–ligand kinetics , pd l1 , ligand (biochemistry) , molecular dynamics , tumor microenvironment , biophysics , immune system , small molecule , blockade , palladium , biochemistry , immunotherapy , catalysis , receptor , biology , immunology , computational chemistry , organic chemistry , ion , physics , quantum mechanics
Immune checkpoint blockade of signaling pathways such as PD‐1/PD‐L1 has recently opened up a new avenue for highly efficient immunotherapeutic strategies to treat cancer. Since tumor microenvironments are characterized by lower pH (5.5‐7.0), pH‐dependent protein‐ligand interactions can be exploited as efficient means to regulate drug affinity and specificity for a variety of malignancies. In this article, we investigate the mechanism and kinetics of pH‐dependent binding and unbinding processes for the PD‐1/PD‐L1 checkpoint pair employing classical molecular dynamics simulations. Two representative pH levels corresponding to circumneutral physiological conditions of blood (pH 7.4) and acidic tumor microenvironment (pH 5.5) are considered. Our calculations demonstrate that pH plays a key role in protein‐ligand interactions with small pH changes leading to several orders of magnitude increase in binding affinity. By identifying the binding pocket in the PD‐1/PD‐L1 complex, we show a pivotal role of the His68 protonation state of PD‐1in the complex stabilization at low pH. The results on the reaction rate constants are in qualitative agreement with available experimental data. The obtained molecular details are important for further engineering of binding/unbinding kinetics to formulate more efficient immune checkpoint blockade strategies.