A computational protocol for the calculation of the standard reduction potential of iron complexes: application to Fe2+/3+-Aβ model systems relevant to Alzheimer's disease

Abstract

Iron complexes play a key role in several biological processes, and they are also related to the development of neurological disorders, such as Alzheimer's and Parkinson's diseases. One of the main properties involved in these processes is the standard reduction potential (SRP) of iron complexes. However, the calculation of this property is challenging, mainly due to problems in the electronic structure description, solvent effects and the thermodynamic cycles used for its calculation. In this work, we proposed a computational protocol for the calculation of SRPs of iron complexes by evaluating a wide range of density functionals for the electronic structure description, two implicit solvent models with varying radii and two thermodynamic cycles. Results show that the M06L density functional in combination with the SMD solvation model and the isodesmic method provides good results compared with SRP experimental values for a set of iron complexes. Finally, this protocol was applied to three Fe^2+/3+-Aβ model systems involved in the development of Alzheimer's disease and the obtained SRP values are in good agreement with those reported previously by means of MP2 calculations.

Fig. 1. Catalytic cycle of ROS formation mediated by Fe^2+/3+-Aβ complexes.

Fig. 2. Structure of most stable (a) Fe³⁺-Aβ and (b) Fe²⁺-Aβ model systems. Adapted from Alí-Torres et al.

Fig. 3. Heatmap for DFT functionals and basis sets. Iron third ionization energy experimental value is 707.42 kcal mol⁻¹.

Fig. 4. Calculated SRP of [Fe(H₂O)₆]³⁺ complex at (a) M06/cc-pVQZ(Fe)-6-31+G(d,p)(O, H); (b) M06L/cc-pVDZ(Fe)-6-31+G(d,p)(O, H); (c) M06/6-31+G(d,p); (d) B3LYP/6-31+G(d,p) levels of theory. Experimental SRP for [Fe(H₂O)₆]³⁺ is 0.77 V (solid black line).

Fig. 5. Fe^2+/3+ complexes used in the training set for the calibration process of SRP.

Scheme 1. Born–Haber cycle to calculate the SRP of iron complexes.

Fig. 6. Calculated SRP for the iron complexes in Fig. 5 using M06L/cc-pVDZ(Fe)+6-31+G(d,p) (C,N,H,O); Data in blue: SMD; data in orange: PCM with Pauling radii (scale factor: 1.05). (a) Direct method with 17 molecules; (b) direct method with 10 molecules used in the isodesmic calculations; (c) isodesmic method with 10 molecules.

Fig. 7. Optimized geometries and calculated SRP values for a series of representative Fe^3+/2+-Aβ model systems. For all the Fe³⁺ complexes the sextet spin-state is the ground state while for Fe²⁺ is the quintet.