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In molecular modeling the description of the interactions between molecules forms the basis for a correct prediction of macroscopic observables. Here, we derive atomic charges from the implicitly polarized electron density of 11 molecules in the SAMPL6 challenge using the Hirshfeld-I and Minimal Basis Set Iterative Stockholder (MBIS) partitioning method. These atomic charges combined with other parameters in the GAFF force field and different water/octanol models were then used in alchemical free energy calculations to obtain hydration and solvation free energies, which after correction for the polarization cost, result in the blind prediction of the partition coefficient. From the tested partitioning methods and water models the S-MBIS atomic charges with the TIP3P water model presented the smallest deviation from the experiment. Conformational dependence of the free energies and the energetic cost associated with the polarization of the electron density are discussed. [ABSTRACT FROM AUTHOR]

The mean reaction force is introduced as the negative derivative of the free energy along a predefined reaction path. In analogy to the reaction force, this descriptor allows detailed characterization of different processes of the reaction mechanism and the assignment of electronic and structural free energy contributions to activation barriers. Due to its free energy dependence, the mean reaction force represents a new tool to study the influence of the environment on the reaction mechanism. Moreover, it enables the separation of catalytic effects in structural and electronic components responsible for the free energy barrier reduction of a reaction. To validate the method, the intramolecular proton transfer in tryptophan was studied in the gas phase, in aqueous solution and at the vacuum-water interface employing molecular dynamics simulation in combination with ab initio calculations and the quantum molecular/molecular mechanics (QM/MM) methodology. The obtained results were compared to static vacuum and continuum calculations. The mean reaction force distinguishes structural rearrangements as the dominant free energy component to reach the transition state from the neutral form, whereas electronic reorganization predominates the activation of the zwitterion in aqueous solution. In addition, it identifies the origin of the reduction of the activation barrier for desolvated functional groups at the water-vacuum interface as the absence of hydrogen bonds which stabilize charge delocalized species. [ABSTRACT FROM AUTHOR]

Grid is a free and open-source Python library for constructing numerical grids to integrate, interpolate, and differentiate functions (e.g., molecular properties), with a strong emphasis on facilitating these operations in computational chemistry and conceptual density functional theory. Although designed, maintained, and released as a stand-alone Python library, Grid was originally developed for molecular integration, interpolation, and solving the Poisson equation in the HORTON and ChemTools packages. Grid is designed to be easy to use, extend, and maintain; this is why we use Python and adopt many principles of modern software development, including comprehensive documentation, extensive testing, continuous integration/delivery protocols, and package management. We leverage popular scientific packages, such as NumPy and SciPy, to ensure high efficiency and optimized performance in grid development. This article is the official release note of the Grid library showcasing its unique functionality and scope. [ABSTRACT FROM AUTHOR]

We develop a variational procedure for the iterative Hirshfeld (HI) partitioning scheme. The main practical advantage of having a variational framework is that it provides a formal and straightforward approach for imposing constraints (e.g., fixed charges on certain atoms or molecular fragments) when computing HI atoms and their properties. Unlike many other variants of the Hirshfeld partitioning scheme, HI charges do not arise naturally from the information-theoretic framework, but only as a reverse-engineered construction of the objective function. However, the procedure we use is quite general and could be applied to other problems as well. We also prove that there is always at least one solution to the HI equations, but we could not prove that its self-consistent equations would always converge for any given initial pro-atom charges. Our numerical assessment of the constrained iterative Hirshfeld method shows that it satisfies many desirable traits of atoms in molecules and has the potential to surpass existing approaches for adding constraints when computing atomic properties. [ABSTRACT FROM AUTHOR]

HORTON is a free and open-source electronic-structure package written primarily in Python 3 with some underlying C++ components. While HORTON's development has been mainly directed by the research interests of its leading contributing groups, it is designed to be easily modified, extended, and used by other developers of quantum chemistry methods or post-processing techniques. Most importantly, HORTON adheres to modern principles of software development, including modularity, readability, flexibility, comprehensive documentation, automatic testing, version control, and quality-assurance protocols. This article explains how the principles and structure of HORTON have evolved since we started developing it more than a decade ago. We review the features and functionality of the latest HORTON release (version 2.3) and discuss how HORTON is evolving to support electronic structure theory research for the next decade. [ABSTRACT FROM AUTHOR]

Conformational changes in enzymes and their role in their catalytic activity have been thoroughly addressed experimentally and theoretically. There is a vivid discussion in the field of enzyme catalysis on whether conformational changes of the enzyme are coupled to catalysis, or whether transition state stabilization through the preorganized protein and its electrostatic properties govern the catalysis. In this study, an additional contribution to the catalysis of one specific enzyme, Pin1, is proposed, which arises from its conformational selection of the peptide substrate from aqueous solution with the lowest activation barrier. The most stable conformers of the reactant (cis) and product (trans) peptide were identified through molecular dynamics simulations in combination with metadynamics. The cis-trans isomerization reaction was studied with quantum mechanical/molecular mechanical molecular dynamics simulations and density functional theory together with the mean reaction force, which allows us to separate structural and electronic contributions to the activation barrier. Our results show that enzyme Pin1 binds the trans isomer in the conformation of the peptide with the smallest activation barrier and reduces the barrier further through specific substrate-enzyme interactions, as we have shown previously. The activation barrier of the cis peptide is independent of the conformer and remains unchanged in the enzyme. [ABSTRACT FROM AUTHOR]

Proton transfer reactions present a key step in many biological and chemical processes. Here, we focused on the electronic changes in the proton transfer reactions of the four DNA bases. In combination with the previous structural analysis the reaction electronic flux together with local descriptors as the Hirshfeld-I charges allow us to identify chemical events and rationalize the underlying reaction mechanism. Our results show that imine-enamine in adenine and citosyne, and keto-enol tautomerizations in thymine and guanine have different reaction mechanisms. The former involve net structural rearrangements driven by favored electrostatic interactions between the proton and the acceptor atom whereas the keto-enol tautomerizations require electronic changes reflected in the reaction electronic flux and changes in the NBO bond orders which favour the proton transfer reaction. [ABSTRACT FROM AUTHOR]

S-Adenosylmethionine (AdoMet) is involved in many biological processes as cofactor in enzymes transferring its sulfonium methyl group to various substrates. Additionally, it is used as drug and nutritional supplement to reduce the pain in osteoarthritis and against depression. Due to the biological relevance of AdoMet it has been part of various computational simulation studies and will also be in the future. However, to our knowledge no rigorous force field parameter development for its simulation in biological systems has been reported. Here, we use electronic structure calculations combined with molecular dynamics simulations in explicit solvent to develop force field parameters compatible with the AMBER99 force field. Additionally, we propose new dynamic Hirshfeld-I atomic charges which are derived from the polarized electron density of AdoMet in aqueous solution to describe its electrostatic interactions in biological systems. The validation of the force field parameters and the atomic charges is performed against experimental interproton NOE distances of AdoMet in aqueous solution and crystal structures of AdoMet in the cavity of three representative proteins. Graphical Abstract: A S-Adenosylmethionine force field was developed together with Dynamic Hirshfeld-I charges (shown color coded in figure) and validated against various experimental data. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Pin1 is an enzyme that specificallycatalyzes the cis–transisomerization of prolineamide bonds in peptides that contain aphosphorylated threonine or serine residue in the position precedingproline. In the cell, the isomerization reaction is associated withcellular signaling and has been related to diseases such as Alzheimerand cancer. The catalytic mechanism by which Pin1 accelerates theisomerization reaction, however, is still unknown. In this study,we use molecular dynamics simulation in combination with the QM/MMmethodology to disclose the influence of the residues Ser-154 andCys-113 in the enzyme and the phosphorylated threonine residue inthe peptide on the reaction mechanism. To account for the correctelectrostatic interaction between the three residues and the reactivecenter, we derive atomic charges that account for the varying electrostaticfield in the catalytic cavity. Different methods based on reproducingthe molecular electrostatic potential or an atoms in molecules approachwere investigated. Finally, the reaction mechanism is analyzed withthe mean reaction force and the influence of the three residues isdisclosed. Our results show that Pin1 specifically catalyzes the isomerizationof the transconformer in a jump-rope type of motion,as suggested by us and confirmed experimentally by others. This isaccomplished by anchoring the threonine phosphate residue on one endof the peptide through electrostatic interactions with the basic triadof the enzyme and at the other end through specific enzyme–peptidehydrogen bonds. Cys-113 reduces the structural contribution to theactivation free energy through the stabilization of the cisconformer, and Ser-154 in combination with Gln-131 assist in theisomerization reaction of the transisomer. [ABSTRACT FROM AUTHOR]

Pin1 represents an enzyme that specifically catalyzesthe isomerizationof peptide bonds between phosphorylated threonine or serine residuesand proline. Despite its relevance as molecular timer in a numberof biological processes related to cancer and Alzheimer disease, adetailed understanding of the factors contributing to the catalysisis still missing. In this study, we employ extensive QM/MM moleculardynamics simulations in combination with the mean reaction force (MRF)to discern the influence of the enzyme on the reaction mechanism andthe origin of the catalysis. As a recently introduced method, theMRF separates the activation free energy barrier to reach the transitionstate into structural and electronic contributions providing a moredetailed description of the enzyme’s function. As a reference,we first study the isomerization starting from the cis form in solutionand obtain a free energy barrier and a reaction free energy, whichare in agreement with previous studies and experiment. With the newmean reaction force method, intramolecular hydrogen bonds in the peptidewere identified that stabilize the transition state and reduce theelectronic contribution to the free energy barrier. To elucidate themechanism of catalysis of Pin1, the reaction in solution and in thecatalytic cavity of the enzyme were compared. Both yield the samefree energy barrier for the isomerization of the cis form, but withdifferent decomposition in structural and electronic contributionsby the mean reaction force. The enzyme reduces the energy requiredfor structural rearrangements to reach the transition state, pointingto a destabilization of the reactant, but increases the electroniccontribution to the barrier through specific enzyme–peptidehydrogen bonds. In the reverse reaction, the isomerization of thetrans form, the enzyme alters the energetics and the mechanism ofthe reaction considerably. Unfavorable enzyme–peptide interactionsin the catalytic cavity during the isomerization change the reactioncoordinate, resulting in two minima with small energy differencesto the transition state. These small free energy barriers should inprinciple make the reaction feasible at room temperature once theconformer is bound in the right conformation. [ABSTRACT FROM AUTHOR]

The role of water in the proton transfer mechanism between the carboxylic and the amino group in tryptophan was studied through the direct, intramolecular reaction in presence of a continuum and the single water molecule mediated, intermolecular reaction in vacuum and in presence of a continuum. The introduction of the continuum reduced the activation barriers for the proton transfer from the neutral form and stabilized the zwitterion in both cases. The reaction force and the reaction electronic flux along the intrinsic reaction coordinate allowed in combination with a Natural Bond Order Analysis a more detailed description of the influence of water on the reaction mechanism. Represented as a continuum model, water reduced the energy required for bond reorganization and did not alter the first part of the intermolecular reaction, characterized through the approximation of the water molecule to the functional groups of the amino acid and a polarization of the system. The absence of a water molecule in the intramolecular proton transfer with continuum changed the reaction coordinate to a reduction of the angle between the functional groups of the amino acid leaving the energy required for bond formation unaffected. Thus, the smaller activation barrier obtained in the direct intramolecular proton transfer with continuum model in comparison to the water mediated reaction, originates from the energetically more favorable angle reduction in comparison the approximation of a water molecule. © 2010 Wiley Periodicals, Inc. J Comput Chem 2010 [ABSTRACT FROM AUTHOR]

Peroxides play a central role in many chemical and biological processes such as the Fenton reaction. The relevance of these compounds lies in the low stability of the O–O bond which upon dissociation results in radical species able to initiate various chemical or biological processes. In this work, a set of 64 DFT functional-basis set combinations has been validated in terms of their capability to describe bond dissociation energies (BDE) for the O–O bond in a database of 14 ROOH peroxides for which experimental values of BDE are available. Moreover, the electronic contributions to the BDE were obtained for four of the peroxides and the anion H 2 O 2 - at the CBS limit at CCSD(T) level with Dunning's basis sets up to triple- ζ quality providing a reference value for the hydrogen peroxide anion as a model. Almost all the functionals considered here yielded mean absolute deviations around 5.0 kcal mol - 1 . The smallest values were observed for the ω B97 family and the Minnesota M11 functional with a marked basis set dependence. Despite the mean deviation, order relations among BDE experimental values of peroxides were also considered. The ω B97 family was able to reproduce the relations correctly whereas other functionals presented a marked dependence on the chemical nature of the R group. Interestingly, M11 functional did not show a very good agreement with the established order despite its good performance in the mean error. The obtained results support the use of similar validation strategies for proper prediction of BDE or other molecular properties by DFT methods in subsequent related studies. [ABSTRACT FROM AUTHOR]

We consider the problem of defining an appropriate local descriptor corresponding to an arbitrary global descriptor. Although it does not seem easy to rigorously and uniquely define local analogues of derived global descriptors (e.g., the electrophilicity) or the fundamental global descriptors associated with the canonical ensemble (e.g., the hardness), the local response of these global descriptors can be defined unambiguously. We look at the local response of the global electrophilicity and compare it to the conventional, ad hoc, definition of the local electrophilicity. The local response of global nucleofugality and electrofugality is also discussed. [ABSTRACT FROM AUTHOR]

Nowadays, the search for efficient methods able to reduce the high atmospheric carbon dioxide concentration has turned into a very dynamic research area. Several environmental problems have been closely associated with the high atmospheric level of this greenhouse gas. Here, a novel system based on the use of surface-functionalized silicon quantum dots (sf-SiQDs) is theoretically proposed as a versatile device to bind carbon dioxide. Within this approach, carbon dioxide trapping is modulated by a photoinduced charge redistribution between the capping molecule and the silicon quantum dots (SiQDs). The chemical and electronic properties of the proposed SiQDs have been studied with a Density Functional Theory and Density Functional Tight-Binding (DFTB) approach along with a time-dependent model based on the DFTB framework. To the best of our knowledge, this is the first report that proposes and explores the potential application of a versatile and friendly device based on the use of sf-SiQDs for photochemically activated carbon dioxide fixation. [ABSTRACT FROM AUTHOR]

IOData is a free and open‐source Python library for parsing, storing, and converting various file formats commonly used by quantum chemistry, molecular dynamics, and plane‐wave density‐functional‐theory software programs. In addition, IOData supports a flexible framework for generating input files for various software packages. While designed and released for stand‐alone use, its original purpose was to facilitate the interoperability of various modules in the HORTON and ChemTools software packages with external (third‐party) molecular quantum chemistry and solid‐state density‐functional‐theory packages. IOData is designed to be easy to use, maintain, and extend; this is why we wrote IOData in Python and adopted many principles of modern software development, including comprehensive documentation, extensive testing, continuous integration/delivery protocols, and package management. This article is the official release note of the IOData library. [ABSTRACT FROM AUTHOR]

Ribulose 1,5‐bisphosphate carboxylase‐oxygenase (RuBisCO) is the main enzyme involved in atmospheric carbon dioxide (CO2) fixation in the biosphere. This enzyme catalyzes a set of five chemical steps that take place in the same active‐site within magnesium (II) coordination sphere. Here, a set of electronic structure benchmark calculations have been carried out on a reaction path proposed by Gready et al. by means of the projector‐based embedding approach. Activation and reaction energies for all main steps catalyzed by RuBisCO have been calculated at the MP2, SCS‐MP2, CCSD, and CCSD(T)/aug‐cc‐pVDZ and cc‐pVDZ levels of theory. The treatment of the magnesium cation with post‐HF methods is explored to determine the nature of its involvement in the mechanism. With the high‐level ab initio values as a reference, we tested the performance of a set of density functional theory (DFT) exchange‐correlation (xc) functionals in reproducing the reaction energetics of RuBisCO carboxylase activity on a set of model fragments. Different DFT xc‐functionals show large variation in activation and reaction energies. Activation and reaction energies computed at the B3LYP level are close to the reference SCS‐MP2 results for carboxylation, hydration and protonation reactions. However, for the carbon–carbon bond dissociation reaction, B3LYP and other functionals give results that differ significantly from the ab initio reference values. The results show the applicability of the projector‐based embedding approach to metalloenzymes. This technique removes the uncertainty associated with the selection of different DFT xc‐functionals and so can overcome some of inherent limitations of DFT calculations, complementing, and potentially adding to modeling of enzyme reaction mechanisms with DFT methods. [ABSTRACT FROM AUTHOR]

Carboxylases are biocatalysts that capture and convert carbon dioxide (CO2) under mild conditions and atmospheric concentrations at a scale of more than 400 Gt annually. However, how these enzymes bind and control the gaseous CO2 molecule during catalysis is only poorly understood. One of the most efficient classes of carboxylating enzymes are enoyl-CoA carboxylases/reductases (Ecrs), which outcompete the plant enzyme RuBisCO in catalytic efficiency and fidelity by more than an order of magnitude. Here we investigated the interactions of CO2 within the active site of Ecr from Kitasatospora setae. Combining experimental biochemistry, protein crystallography, and advanced computer simulations we show that 4 amino acids, N81, F170, E171, and H365, are required to create a highly efficient CO2-fixing enzyme. Together, these 4 residues anchor and position the CO2 molecule for the attack by a reactive enolate created during the catalytic cycle. Notably, a highly ordered water molecule plays an important role in an active site that is otherwise carefully shielded from water, which is detrimental to CO2 fixation. Altogether, our study reveals unprecedented molecular details of selective CO2 binding and C-Cbond formation during the catalytic cycle of nature's most efficient CO2-fixing enzyme. This knowledge provides the basis for the future development of catalytic frameworks for the capture and conversion of CO2 in biology and chemistry. [ABSTRACT FROM AUTHOR]

Carboxylation reactions represent a very special class of chemical reactions that is characterized by the presence of a carbon dioxide (CO2) molecule as reactive species within its global chemical equation. These reactions work as fundamental gear to accomplish the CO2 fixation and thus to build up more complex molecules through different technological and biochemical processes. In this context, a correct description of the CO2 electronic structure turns out to be crucial to study the chemical and electronic properties associated with this kind of reactions. Here, a systematic study of CO2 electronic structure and its contribution to different carboxylation reaction electronic energies has been carried out by means of several high‐level ab initio post‐Hartree Fock (post‐HF) and density functional theory (DFT) calculations for a set of biochemistry and inorganic systems. We have found that for a correct description of the CO2 electronic correlation energy it is necessary to include post‐CCSD(T) contributions (beyond the gold standard). These high‐order excitations are required to properly describe the interactions of the four π‐electrons associated with the two degenerated π‐molecular orbitals of the CO2 molecule. Likewise, our results show that in some reactions it is possible to obtain accurate reaction electronic energy values with computationally less demanding methods when the error in the electronic correlation energy compensates between reactants and products. Furthermore, the provided post‐HF reference values allowed to validating different DFT exchange‐correlation functionals combined with different basis sets for chemical reactions that are relevant in biochemical CO2 fixing enzymes. © 2019 Wiley Periodicals, Inc. Schematic representation of the electronic correlation energy for reactants and products in two representative carboxylation reactions. The height of each box represents the total electronic correlation energy calculated at CBS limit and the respective color shows the amount recovered by a specific electronic structure method. Errors in the calculated reaction energies are much larger when no error compensation between reactants and products takes place. [ABSTRACT FROM AUTHOR]

Many population analysis methods are based on the precept that molecules should be built from fragments (typically atoms) that maximally resemble the isolated fragment. The resulting molecular building blocks are intuitive (because they maximally resemble well-understood systems) and transferable (because if two molecular fragments both resemble an isolated fragment, they necessarily resemble each other). Information theory is one way to measure the deviation between molecular fragments and their isolated counterparts, and it is a way that lends itself to interpretation. For example, one can analyze the relative importance of electron transfer and polarization of the fragments. We present key features, advantages, and disadvantages of the information-theoretic approach. We also codify existing information-theoretic partitioning methods in a way that clarifies the enormous freedom one has within the information-theoretic ansatz. [ABSTRACT FROM AUTHOR]

We present explicit formulas for arbitrary-order derivatives of the energy, grand potential, electron density, and higher-order response functions with respect to the number of electrons, and the chemical potential for any smooth and differentiable model of the energy versus the number of electrons. The resulting expressions for global reactivity descriptors (hyperhardnesses and hypersoftnesses), local reactivity descriptors (hyperFukui functions and local hypersoftnesses), and nonlocal response functions are easy to evaluate computationally. Specifically, the explicit formulas for global/local/nonlocal hypersoftnesses of arbitrary order are derived using Bell polynomials. Explicit expressions for global and local hypersoftness indicators up to fifth order are presented. [ABSTRACT FROM AUTHOR]

A series of five crystal structures of 1 : 1 halogen-bonded complexes were obtained from 4-[5-(4-alkoxyphenyl)-1,3,4-oxadiazole-2-yl]pyridine and 1,3,5-trifluorotriiodobenzene. Electronic structure calculations show that the N(oxadiazole)…I interaction in the new synthon is as strong as the classic N(pyridine)…I interaction. Oxygen to sulfur atom subsitution on the oxadiazole ring results in a different supramolecular packing where the N(pyridine)…I interaction is favored, which could be rationalized by the changes in the molecular electrostatic potential predicted from the theoretical calculations. [ABSTRACT FROM AUTHOR]

Using the recently solved crystal structure of the human adenosine A2Areceptor, we applied MM/PBSA to compare the binding modes of caffeine with those of the high-affinity selective antagonist ZM241385. MD simulations were performed in the environment of the lipid membrane bilayer. Four low-energy binding modes of caffeine-A2Awere found, all of which had similar energies. Assuming an equal contribution of each binding mode of caffeine, the computed binding free energy difference between caffeine and ZM241385 is −2.4 kcal/mol, which compares favorably with the experimental value, −3.6 kcal/mol. The configurational entropy contribution of −0.9 kcal/mol from multiple binding modes of caffeine helps explain how a small molecule like caffeine can compete with a significantly larger molecule, ZM241385, which can form many more interactions with the receptor. We also performed residue-wise energy decomposition and found that Phe168, Leu249, and Ile274 contribute most significantly to the binding modes of caffeine and ZM241385. [ABSTRACT FROM AUTHOR]

Global and local descriptors of chemical reactivity can be derived from conceptual density functional theory. Their explicit form, however, depends on how the energy is defined as a function of the number of electrons. Within the existing interpolation models, here, the quadratic and the linear energy model were used to derive global descriptors as the electrophilicity and nucleophilicity (defined as the negative of the ionization potential) and local descriptors employing either the corresponding condensed Fukui function in the linear model or the local response of the global descriptor in the quadratic model. The ability of these descriptors to predict the reactivity of molecules with more than one reactive site was first studied on a set of α, β‐unsaturated ketones, where experimental rate constants for the nucleophilic attack is known. With the validated descriptors the reactivity of α, β‐unsaturated carboxylic compounds with different heteroatoms as α, β‐unsaturated thioesters, esters, and amides was addressed as alternative substrates for enzymatic CO2 fixation. Carbon dioxide fixation involves the reduction of the neutral α, β‐unsaturated carboxylic compounds by a nucleophilic attack of a hydride anion from NADPH and the following electrophilic attack by carbon dioxide. It was found that condensed values of the linear Fukui function within the fragment of molecular response approximation describe best the reactivity of α, β‐unsaturated ketones. For the two relevant processes involved in CO2 fixation the amides present the largest reactivity in vacuum and in aqueous solution compared to the esters and thioesters and may, therefore, serve as alternative substrates of carboxylases. Different global and local reactivity descriptors based on conceptual DFT were used to study the nucleophilic attack on α, β‐unsaturated organic compounds. From the two possible reactive sites (red circles) the condensed Fukui function f+(r) computed by the fragment of molecular response approach locates correctly the preferred reaction site and correlates with the experimental reactivity trend. [ABSTRACT FROM AUTHOR]

Hydroxyl radical reduction and peroxide bond breaking in hydrogen peroxide are reactions involved in various processes such as the Fenton reaction, which has applications as e.g. groundwater remediation. Here, we study these two reactions from a thermodynamical point of view through the bond dissociation energy (BDE) of the O-O bond in hydrogen peroxide and the electron affinity (EA) of the hydroxyl radical. High-level ab-initio calculations at the complete basis set (CBS) limit were carried out, and the performance of different DFT-based methods was addressed by following a specific classification on the basis of the Jacob’s ladder in combination with various Pople’s basis sets. The ab-initio calculations at the CBS limit are in agreement with experimental reference data and identify a significant contribution of the electron correlation energy to the BDE and EA. The studied DFT-based methods were able to reproduce the ab-initio reference values, although no functional was particularly detected as the best for both reactions. The inclusion of certain percentage of Hartree-Fock (HF) exchange in DFT functionals leads in most cases to smaller BDE and EA values, which might be related to the poor description of the two reactions by the HF method. Considering the computational cost, DFT methods provide better BDE and EA values than HF methods with an accuracy comparable to the MP2 or CCSD level of theory. Additionally, the quality of the hydrogen peroxide, hydroxyl radical and hydroxyl anion structures obtained from these functionals was compared to experimental reference data. In general, bond lengths were well reproduced and the errors in the angles were between one and two degrees with some systematic trend with respect to the basis set’s size. From our results we conclude that DFT methods present a computationally less expensive alternative to describe these two reactions that play a role in the Fenton reaction. The benchmark that is carried out in this study provides a systematic validation of various approximated Exc[ρ] functionals combined with different basis sets, which could serve as a stepping-stone for future research on the Fenton reaction. [ABSTRACT FROM AUTHOR]