Probing the binding interactions between perfluoroalkyl carboxylic acids and adenosine A2A receptors by spectroscopic techniques, molecular simulations and quantum chemistry

Abstract

The binding interactions of perfluorobutyric acid (PFBA), heptafluorobutyric anhydride (HFBA), and ethyl heptafluorobutyrate (NSC3936) with the adenosine A2A receptor (A2AR) were investigated using multiple-spectral (fluorescence, ultraviolet–visible (UV–Vis) absorption, three-dimensional (3D) fluorescence, and Fourier Transform infrared (FT-IR) spectroscopy) and computational simulation methods. Steady-state fluorescence and UV–visible spectroscopy indicated that PFBA, HFBA, and NSC3936 caused an intrinsic fluorescence quenching of A2AR by static quenching and non-radiative energy transfer. The results of 3D fluorescence and FT-IR spectroscopy showed that the presence of PFBA, HFBA, and NSC3936 induced changes in the secondary structure of A2AR. Combined with thermodynamic analysis, molecular docking and quantum chemistry investigations, our results suggest that the association of PFBA, HFBA, and NSC3936 with A2AR was driven by hydrophobic forces and the formation of hydrogen bonds (H-bonds). The binding constants for the three PFCAs studied range from 8.27 × 106 L·mol−1 to 1.80 × 107 L·mol−1 at 298 K. Molecular dynamics (MD) simulations indicated that A2AR formed stable complexes with PFBA, HFBA, and NSC3936, and validated the existence of electrostatic interactions in the HFBA-A2AR complex. Furthermore, the results from the MD simulations were consistent with the thermodynamic analysis results.