Computational Electrochemistry as a Reliable Probe of Experimentally Elusive Mononuclear Nonheme Iron Species

Despite the growing number of reported Fe^IVO complexes, an unambiguous experimental characterization of their redox properties, such as one-electron reduction potentials, remains a challenging task. To this aim, we describe an efficient and straightforward theoretical protocol for accurate calculations of redox potentials and calibrate the protocol on a set of diverse 37 mononuclear nonheme iron (NHFe) redox couples. It is shown that the methodology, further applied to a set of 10 Fe^IVO species, not only serves for near-quantitative predictions of reduction potentials, but also is an elegant tool for interpretation of the experimental electrochemical data. The general need for such a computational methodology is illustrated on the prototypical example of the (N4Py)­Fe^IVO complex, whose electrochemistry has been studied for many years and still raises many questions

Accurate Prediction of One-Electron Reduction Potentials in Aqueous Solution by Variable-Temperature H‑Atom Addition/Abstraction Methodology

A robust and efficient theoretical approach for calculation of the reduction potentials of charged species in aqueous solution is presented. Within this approach, the reduction potential of a charged complex (with a charge |<i>n|</i> ≥ 2) is probed by means of the reduction potential of its neutralized (protonated/deprotonated) cognate, employing one or several H-atom addition/abstraction thermodynamic cycles. This includes a separation of one-electron reduction from protonation/deprotonation through the temperature dependence. The accuracy of the method has been assessed for the set of 15 transition-metal complexes that are considered as highly challenging systems for computational electrochemistry. Unlike the standard computational protocol(s), the presented approach yields results that are in excellent agreement with experimental electrochemical data. Last but not least, the applicability and limitations of the approach are thoroughly discussed

Accurate Prediction of One-Electron Reduction Potentials in Aqueous Solution by Variable-Temperature H‑Atom Addition/Abstraction Methodology

A robust and efficient theoretical approach for calculation of the reduction potentials of charged species in aqueous solution is presented. Within this approach, the reduction potential of a charged complex (with a charge |<i>n|</i> ≥ 2) is probed by means of the reduction potential of its neutralized (protonated/deprotonated) cognate, employing one or several H-atom addition/abstraction thermodynamic cycles. This includes a separation of one-electron reduction from protonation/deprotonation through the temperature dependence. The accuracy of the method has been assessed for the set of 15 transition-metal complexes that are considered as highly challenging systems for computational electrochemistry. Unlike the standard computational protocol(s), the presented approach yields results that are in excellent agreement with experimental electrochemical data. Last but not least, the applicability and limitations of the approach are thoroughly discussed

Computational Electrochemistry as a Reliable Probe of Experimentally Elusive Mononuclear Nonheme Iron Species

Despite the growing number of reported Fe^IVO complexes, an unambiguous experimental characterization of their redox properties, such as one-electron reduction potentials, remains a challenging task. To this aim, we describe an efficient and straightforward theoretical protocol for accurate calculations of redox potentials and calibrate the protocol on a set of diverse 37 mononuclear nonheme iron (NHFe) redox couples. It is shown that the methodology, further applied to a set of 10 Fe^IVO species, not only serves for near-quantitative predictions of reduction potentials, but also is an elegant tool for interpretation of the experimental electrochemical data. The general need for such a computational methodology is illustrated on the prototypical example of the (N4Py)­Fe^IVO complex, whose electrochemistry has been studied for many years and still raises many questions

Macrocycle Conformational Sampling by DFT-D3/COSMO-RS Methodology

To find and calibrate a robust and reliable computational protocol for mapping conformational space of medium-sized molecules, exhaustive conformational sampling has been carried out for a series of seven <i>macrocyclic</i> compounds of varying ring size and one acyclic analogue. While five of them were taken from the MD/LLMOD/force field study by Shelley and co-workers (Watts, K. S.; Dalal, P.; Tebben, A. J.; Cheney, D. L.; Shelley, J. C. Macrocycle Conformational Sampling with MacroModel. J. Chem. Inf. Model. 2014, 54, 2680−2696), three represent potential macrocyclic inhibitors of human cyclophilin A. The free energy values (<i>G</i>_{DFT/COSMO‑RS}) for all of the conformers of each compound were obtained by a composite protocol based on <i>in vacuo</i> quantum mechanics (DFT-D3 method in a large basis set), standard gas-phase thermodynamics, and the COSMO-RS solvation model. The <i>G</i>_{DFT/COSMO‑RS} values were used as the reference for evaluating the performance of conformational sampling algorithms: standard and extended MD/LLMOD search (simulated-annealing molecular dynamics with low-lying eigenvector following algorithms, employing the OPLS2005 force field plus GBSA solvation) available in MacroModel and plain molecular dynamics (MD) sampling at high temperature (1000 K) using the semiempirical quantum mechanics (SQM) potential SQM­(PM6-D3H4/COSMO) followed by energy minimization of the snapshots. It has been shown that the former protocol (MD/LLMOD) may provide a more complete set of initial structures that ultimately leads to the identification of a greater number of low-energy conformers (as assessed by <i>G</i>_{DFT/COSMO‑RS}) than the latter (i.e., plain SQM MD). The CPU time needed to fully evaluate one medium-sized <i>compound</i> (∼100 atoms, typically resulting in several hundred or a few thousand conformers generated and treated quantum-mechanically) is approximately 1,000–100,000 CPU hours on today’s computers, which transforms to 1–7 days on a small-sized computer cluster with a few hundred CPUs. Finally, our data sets based on the rigorous quantum-chemical approach allow us to formulate a composite conformational sampling protocol with multiple checkpoints and truncation of redundant structural data that offers superior insights at affordable computational cost

Toward Accurate Conformational Energies of Smaller Peptides and Medium-Sized Macrocycles: MPCONF196 Benchmark Energy Data Set

A carefully selected set of acyclic and cyclic model peptides and several other macrocycles, comprising 13 compounds in total, has been used to calibrate the accuracy of the DFT­(-D3) method for conformational energies, employing BP86, PBE0, PBE, B3LYP, BLYP, TPSS, TPSSh, M06-2X, B97-D, OLYP, revPBE, M06-L, SCAN, revTPSS, BH-LYP, and ωB97X-D3 functionals. Both high- and low-energy conformers, 15 or 16 for each compound adding to 196 in total, denoted as the MPCONF196 data set, were included, and the reference values were obtained by the composite protocol, yielding the CCSD­(T)/​CBS extrapolated energies or their DLPNO-CCSD­(T)/​CBS equivalents in the case of larger systems. The latter was shown to be in near-quantitative (∼0.10–0.15 kcal·mol^–1) agreement with the canonical CCSD­(T), provided the TightPNO setting is used, and, therefore, can be used as the reference for larger systems (likely up to 150–200 atoms) for the problem studied here. At the same time, it was found that many D3-corrected DFT functionals provide results of ∼1 kcal·mol^–1 accuracy, which we consider as quite encouraging. This result implies that DFT-D3 methods can be, for example, safely used in efficient conformational sampling algorithms. Specifically, the DFT-D3/​DZVP-DFT level of calculation seems to be the best trade-off between computational cost and accuracy. Based on the calculated data, we have not found any cheaper variant for the treatment of conformational energies, since the semiempirical methods (including DFTB) provide results of inferior accuracy (errors of 3–5 kcal·mol^–1)

Toward Accurate Conformational Energies of Smaller Peptides and Medium-Sized Macrocycles: MPCONF196 Benchmark Energy Data Set

A carefully selected set of acyclic and cyclic model peptides and several other macrocycles, comprising 13 compounds in total, has been used to calibrate the accuracy of the DFT­(-D3) method for conformational energies, employing BP86, PBE0, PBE, B3LYP, BLYP, TPSS, TPSSh, M06-2X, B97-D, OLYP, revPBE, M06-L, SCAN, revTPSS, BH-LYP, and ωB97X-D3 functionals. Both high- and low-energy conformers, 15 or 16 for each compound adding to 196 in total, denoted as the MPCONF196 data set, were included, and the reference values were obtained by the composite protocol, yielding the CCSD­(T)/​CBS extrapolated energies or their DLPNO-CCSD­(T)/​CBS equivalents in the case of larger systems. The latter was shown to be in near-quantitative (∼0.10–0.15 kcal·mol^–1) agreement with the canonical CCSD­(T), provided the TightPNO setting is used, and, therefore, can be used as the reference for larger systems (likely up to 150–200 atoms) for the problem studied here. At the same time, it was found that many D3-corrected DFT functionals provide results of ∼1 kcal·mol^–1 accuracy, which we consider as quite encouraging. This result implies that DFT-D3 methods can be, for example, safely used in efficient conformational sampling algorithms. Specifically, the DFT-D3/​DZVP-DFT level of calculation seems to be the best trade-off between computational cost and accuracy. Based on the calculated data, we have not found any cheaper variant for the treatment of conformational energies, since the semiempirical methods (including DFTB) provide results of inferior accuracy (errors of 3–5 kcal·mol^–1)

Radical Reactions Affecting Polar Groups in Threonine Peptide Ions

Peptide cation-radicals containing the threonine residue undergo radical-induced dissociations upon collisional activation and photon absorption in the 210–400 nm range. Peptide cation-radicals containing a radical defect at the <i>N</i>-terminal residue, [^•Ala-Thr-Ala-Arg+H]⁺, were generated by electron transfer dissociation (ETD) of peptide dications and characterized by UV–vis photodissociation action spectroscopy combined with time-dependent density functional theory (TD-DFT) calculations of absorption spectra, including thermal vibronic band broadening. The action spectrum of [^•Ala-Thr-Ala-Arg+H]⁺ ions was indicative of the canonical structure of an <i>N</i>-terminally deaminated radical whereas isomeric structures differing in the position of the radical defect and amide bond geometry were excluded. This indicated that exothermic electron transfer to threonine peptide ions did not induce radical isomerizations in the fragment cation-radicals. Several isomeric structures, ion–molecule complexes, and transition states for isomerizations and dissociations were generated and analyzed by DFT and Møller–Plesset perturbational ab initio calculations to aid interpretation of the major dissociations by loss of water, hydroxyl radical, C₃H₆NO^•, C₃H₇NO, and backbone cleavages. Born–Oppenheimer molecular dynamics (BOMD) in combination with DFT gradient geometry optimizations and intrinsic reaction coordinate analysis were used to search for low-energy cation-radical conformers and transition states. BOMD was also employed to analyze the reaction trajectory for loss of water from ion–molecule complexes

Near-UV Water Splitting by Cu, Ni, and Co Complexes in the Gas Phase

(2,2′-Bipyridine)­MO⁺ ions (M = Cu, Ni, Co) were generated by collision-induced dissociation and near-UV photodissociation of readily available [(2,2′-bipyridine)­M^II(NO₃)]⁺ ions in the gas phase, and their structure was confirmed by ion–molecule reactions combined with isotope labeling. Upon storage in a quadrupole ion trap, the (2,2′-bipyridine)­MO⁺ ions spontaneously added water, and the formed [(2,2′-bipyridine)­MO + H₂O]⁺ complexes eliminated OH upon further near-UV photodissociation. This reaction sequence can be accomplished at a single laser wavelength in the range of 260–340 nm to achieve stoichiometric homolytic cleavage of gaseous water. Structures, spin states, and electronic excitations of the metal complexes were characterized by ion–molecule reactions using ²H and ¹⁸O labeling, photodissociation action spectroscopy, and density functional theory calculations