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. 2022 Sep 30;27(19):6454.
doi: 10.3390/molecules27196454.

Effects of Environmental and Electric Perturbations on the pKa of Thioredoxin Cysteine 35: A Computational Study

Valeria D'Annibale  1   2 , Donatella Fracassi  3 , Paolo Marracino  4 , Guglielmo D'Inzeo  3 , Marco D'Abramo  1
Affiliations

Effects of Environmental and Electric Perturbations on the pKa of Thioredoxin Cysteine 35: A Computational Study

Valeria D'Annibale et al. Molecules. .

Abstract

Here we present a theoretical-computational study dealing with the evaluation of the pKa of the Cysteine residues in Thioredoxin (TRX) and in its complex with the Thioredoxin-interacting protein (TXNIP). The free energy differences between the anionic and neutral form of the Cysteine 32 and 35 have been evaluated by means of the Perturbed Matrix Method with classical perturbations due to both the environment and an exogenous electric field as provided by Molecular Dynamics (MD) simulations. The evaluation of the free energies allowed us to show that the effect of the perturbing terms is to lower the pKa of Cysteine 32 and Cysteine 35 with respect to the free amino-acid. On the other hand, in the complex TRX-TXNIP, our data show an enhanced stabilization of the neutral reduced form of Cys 35. These results suggest that external electric stimuli higher than 0.02 V/nm can modulate the Cysteine pKa, which can be connected to the tight regulation of the TRX acting as an antioxidant agent.

Keywords: PMM; Thioredoxin; electric field; molecular communications; pKa.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of the complex TRX-TXNIP with a focus on the active site with its CXXC motif.
Figure 2
Figure 2
(a) PCA analysis on the C-α of TRX and TRX-TXNIP; (b) Eigenvector components analysis for the C-α atoms of TRX; (c) analysis of h-bonds between Cys 35 and solvent; (d) solvent accessible surface of the active site in TRX and in TRX-TXNIP. On the right of the figure, the TRX and TRX-TXNIP complex are shown in cartoon representation.
Figure 3
Figure 3
(left) PCA comparis on between TRX and TRX-TXNIP (as reported in Figure 2a); (right) PCA for the C-α of TRX: no field (blue), E = 0.06 V/nm (yellow), E = 0.12 V/nm (violet).
Figure 4
Figure 4
Comparison between the effect of electric field and temperature on Cys 35 in TRX.
See this image and copyright information in PMC

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