Interaction between Juglone and Peptidyl-prolyl Cis-trans Isomerase NIMA-interacting 1 by Spectroscopic Combined with Computational Simulation
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Abstract:
Juglone is an important active substance in Juglandaceae walnut plant nuts chinense (Jugland mandshurica Maxim) and walnut (Juglans regia L), and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is a small molecule proteasome that mainly plays a role in signaling transduction. In order to explore the inhibition mechanism of juglone on Pin1, the interaction between Pin1 and juglone was studied by site-directed mutagenesis, computational simulation techniques and multiple spectroscopy. The fluorescence spectra showed that juglone could effectively quench the endogenous fluorescence of Pin1. At 293 K, the quenching constant (Ksv) was 1.36×104 L/mol, the binding constant was (Ka) 2.32×104 L/mol, and the binding number (n) was 0.85. With the increase of temperature, Ksv and Ka decreased gradually, which indicated that the quenching mechanism was static quenching, and the binding number n was close to 1, which indicated that they could form 1:1 complex. Synchronous fluorescence spectrum revealed that the combination of juglone with Pin1 could decrease the hydrophobicity and increase the polarity of the microenvironment around the tyrosine and tryptophan residues of Pin1. Circular dichroism revealed that the combination of juglone with Pin1 resulted in the reduction of α-helical structure in Pin1. Thermodynamic parameters showed that ΔH=12.97 kJ/mol, ΔS=127.83 J/(mol·K), and ΔG=-24.49 kJ/mol at 293 K, which indicated that juglone and Pin1 could combine spontaneously, and the main action force was hydrophobic action. Molecular docking showed that hydrogen bonds and van der Waals forces also played important roles in the process. Molecular docking, fluorescence titration and molecular dynamics simulation further revealed that catalytic residue Cys113 of Pin1 played a crucial role in the binding of juglone to Pin1.
