Data_Sheet_2_Benchmark of Density Functionals for the Calculation of the Redox Potential of Fe3+/Fe2+ Within Protein Coordination Shells.zip

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, ΔEelecFe3+/Fe2+), 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 ΔEelecFe3+/Fe2+, 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.

铁是一类极为重要的过渡金属，广泛存在于蛋白质中。具体而言，酶催化反应的核心位点常含有铁元素，其参与酶促反应循环，且多参与氧化还原反应——在此类反应中，铁会在最常见的Fe(III)/Fe(II)氧化态之间循环转换。用于研究此类催化反应机制的量子力学（QM）与量子力学/分子力学（QM/MM）计算方法，大多采用密度泛函理论（DFT）来描述化学转化过程。但需注意，密度泛函方法普遍存在体系特异性与性质特异性的计算误差，这为相关研究结果蒙上了不确定性的阴影。本研究针对12种以氨基酸侧链作为配体的铁配位配合物进行建模，并以耦合簇理论单双激发微扰校正/完全基组（CCSD(T)/CBS）方法计算得到的氧化还原性质作为参考基准，评估了主流密度泛函重现该类铁配合物氧化还原性质的准确性——具体为0 K下氧化还原电位的电子分量ΔEelecFe3+/Fe2+。研究表明，多数含有较高哈特利-福克（HF）交换占比的杂化泛函与杂化meta泛函（如BB1K、mPWB1K及mPW1B95），可系统给出ΔEelecFe3+/Fe2+的准确数值，其平均绝对误差（MUE）约为2 kcal/mol。广受应用的B3LYP密度泛函同样具备较高精度，其平均绝对误差为2.51 kcal/mol。综上，本研究可为涉及铁辅因子的酶促反应机制研究中，估算密度泛函方法带来的计算误差提供参考准则，并为同类反应的理论研究选择合适的密度泛函提供依据。