Abstract
Iron is a very important transition metal often found in proteins. In enzymes specifically, it is often found at the core of reaction mechanisms, participating in the reaction cycle, more often than not in oxidation/reduction reactions, where it cycles between its most common Fe(III)/Fe(II) oxidation states. QM and QM/MM computational methods that study these catalytic reaction mechanisms mostly use density functional theory (DFT) to describe the chemical transformations. Unfortunately, density functional is known to be plagued by system-specific and property-specific inaccuracies that cast a shadow of uncertainty over the results. Here we have modeled 12 iron coordination complexes, using ligands that represent amino acid sidechains, and calculated the accuracy with which the most common density functionals reproduce the redox properties of the iron complexes (specifically the electronic component of the redox potential at 0 K, ), using the same property calculated with CCSD(T)/CBS as reference for the evaluation. A number of hybrid and hybrid-meta density functionals, generally with a large % of HF exchange (such as BB1K, mPWB1K, and mPW1B95) provided systematically accurate values for , with MUEs of ~2 kcal/mol. The very popular B3LYP density functional was found to be quite precise as well, with a MUE of 2.51 kcal/mol. Overall, the study provides guidelines to estimate the inaccuracies coming from the density functionals in the study of enzyme reaction mechanisms that involve an iron cofactor, and to choose appropriate density functionals for the study of the same reactions.
Highlights
Iron plays an important role in enzyme catalysis
Extrapolation to this level was done using two different schemes, as described in the methods section of this paper. These values were used in conjunction with the CCSD(T) results in order to extrapolate the energies to the CCSD(T)/complete basis set (CBS) level
Our results show that MP2/CBS energies obtained with scheme I are closer to those calculated with quadruple-zeta basis set than any of the other basis sets, as expected, and that the difference between the CBS and quadruple-zeta basis set is small, as can be confirmed by comparing the values for the mean signed error (MSE) and mean unsigned error (MUE) for each of them
Summary
Iron plays an important role in enzyme catalysis It is present in a wide range of proteins as a cofactor, and intervenes in many biochemical processes, in oxygen transport, and electron transfer. One of the most important characteristics of iron is the fact that it can be found in two stable states of oxidation, Fe2+ and Fe3+ It is this characteristic that allows iron to participate in a wide range of redox reactions (Broderick, 2001). In proteins, it is usually found in the active site, DFT Benchmark for Fe3+/Fe2+ Redox Potential coordinated with the side chains of amino acid residues and/or water molecules. Through evolution, the ligands to which the iron is coordinated were selected so that its redox potential became the most appropriate for the reaction catalyzed by it (Tamames and Ramos, 2010; Liu et al, 2014)
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