Dissociation Free Energy Research Articles

Proton-Coupled Defects Impact O-H Bond Dissociation Free Energies on Metal Oxide Surfaces.

Proton-coupled electron transfer (PCET) reactions on metal oxides require coupling between proton transfer at the solid-liquid interface and electron transfer involving defects at or near the band edge. Herein, hybrid functional periodic density functional theory is used to elucidate the impact of proton-coupled defects on the bond dissociation free energies (BDFEs) of O-H bonds on anatase TiO2 surfaces. These O-H BDFEs are directly related to interfacial PCET thermochemistry. Comparison between geometrically similar O-H bonds associated with different defect types, namely conduction d-band electrons or valence p-band holes, reveals that the BDFEs differ by ∼81 kcal/mol (3.50 eV), comparable to the wide TiO2 band gap. These differences are shown to be determined primarily by differences in electron transfer driving forces, which are analyzed by using band energies and inner-sphere reorganization energies within a Marcus theory framework. These fundamental insights about the impact of proton-coupled defects on PCET thermochemistry at semiconductor surfaces have broad implications for electrocatalysis.

Concerted Multiproton-Multielectron Transfer for the Reduction of O2 to H2O with a Polyoxovanadate Cluster.

The concerted transfer of protons and electrons enables the activation of small-molecule substrates by bypassing energetically costly intermediates. Here, we present the synthesis and characterization of several hydrogenated forms of an organofunctionalized vanadium oxide assembly, [V6O13(TRIOLNO2)2]2-, and their ability to facilitate the concerted transfer of protons and electrons to O2. Electrochemical analysis reveals that the fully reduced cluster is capable of mediating 2e-/2H+ transfer reactions from surface hydroxide ligands, with an average bond dissociation free energy (BDFE) of 61.6 kcal/mol. Complementary stoichiometric experiments with hydrogen-atom-accepting reagents of established bond strengths confirm that the electrochemically established BDFE predicts the 2H+/2e- transfer reactivity of the assembly. Finally, the reactivity of the reduced polyoxovanadate toward O2 reduction is summarized; our results indicate a stepwise reduction of the substrate, proceeding through H2O2 en route to the formation of H2O. Kinetic isotope effect experiments confirm the participation of hydrogen transfer in the rate-determining step of both the reduction of O2 and H2O2. This work constitutes the first example of hydrogen atom transfer for small-molecule activation with reduced polyoxometalates, where both electron and proton originate from the cluster.

Comparison of Thermodynamic, Kinetic Forces for Three NADH Analogues to Release Hydride Ion or Hydrogen Atom in Acetonitrile

AbstractIn this work, the thermodynamic and kinetic forces of three NADH analogues as BNAH, HEH2, and AcrH2, to release hydride ion or hydrogen atom in acetonitrile in chemical reactions were discussed and researched, which was important for chemists to understand the real capacity of hydride‐donating, hydrogen‐atom‐donating of these three compounds. By comparing the bond dissociation free energy [ΔGo(XL)], self‐exchange reaction activation energy [ΔG≠XL/X], and thermo‐kinetic parameter [ΔG≠°(XL)] of these three compounds to release hydride ion or hydrogen atom, it's easy to find that reactions that thermodynamically favorable were not necessarily kinetically favorable. Therefore, it's unreasonable to judge the hydride‐donating ability or hydrogen‐atom‐donating ability of a compound only by its thermodynamic parameter or kinetic parameter. In addition, with these thermodynamic and kinetic parameters, we are better able to select suitable compound as model of NADH which based on different requirement in reactions.

Combining Structural with Functional Model Properties in Iron Synthetic Analogue Complexes for the Active Site in Rabbit Lipoxygenase.

Iron complexes that model the structural and functional properties of the active iron site in rabbit lipoxygenase are described. The ligand sphere of the mononuclear pseudo-octahedral cis-(carboxylato)(hydroxo)iron(III) complex, which is completed by a tetraazamacrocyclic ligand, reproduces the first coordination shell of the active site in the enzyme. In addition, two corresponding iron(II) complexes are presented that differ in the coordination of a water molecule. In their structural and electronic properties, both the (hydroxo)iron(III) and the (aqua)iron(II) complex reflect well the only two essential states found in the enzymatic mechanism of peroxidation of polyunsaturated fatty acids. Furthermore, the ferric complex is shown to undergo hydrogen atom abstraction reactions with O-H and C-H bonds of suitable substrates, and the bond dissociation free energy of the coordinated water ligand of the ferrous complex is determined to be 72.4 kcal·mol-1. Theoretical investigations of the reactivity support a concerted proton-coupled electron transfer mechanism in close analogy to the initial step in the enzymatic mechanism. The propensity of the (hydroxo)iron(III) complex to undergo H atom abstraction reactions is the basis for its catalytic function in the aerobic peroxidation of 2,4,6-tri(tert-butyl)phenol and its role as a radical initiator in the reaction of dihydroanthracene with oxygen.

Visible light enables catalytic formation of weak chemical bonds with molecular hydrogen.

The synthesis of weak chemical bonds at or near thermodynamic potential is a fundamental challenge in chemistry, with applications ranging from catalysis to biology to energy science. Proton-coupled electron transfer using molecular hydrogen is an attractive strategy for synthesizing weak element-hydrogen bonds, but the intrinsic thermodynamics presents a challenge for reactivity. Here we describe the direct photocatalytic synthesis of extremely weak element-hydrogen bonds of metal amido and metal imido complexes, as well as organic compounds with bond dissociation free energies as low as 31 kcal mol-1. Key to this approach is the bifunctional behaviour of the chromophoric iridium hydride photocatalyst. Activation of molecular hydrogen occurs in the ground state and the resulting iridium hydride harvests visible light to enable spontaneous formation of weak chemical bonds near thermodynamic potential with no by-products. Photophysical and mechanistic studies corroborate radical-based reaction pathways and highlight the uniqueness of this photodriven approach in promoting new catalytic chemistry.

Calculation of CYP450 protein-ligand binding and dissociation free energy paths.

The function of an enzyme depends on its dynamic structure, and the catalytic mechanism has long been an active focus of research. The principle for interpreting protein selectivity and fidelity stems from optimization of the active site upon protein-substrate complexation, i.e., a lock-and-key configuration, on which most protein-substrate molecule binding recognition, and hence drug discovery, relies. Yet another thought has been to incorporate the protein folding interior tunnels for stereo- and regio-selectivity along the protein-substrate or protein-ligand/inhibitor binding process. Free energy calculations provide valuable information for molecular recognition and protein-ligand binding dynamics and kinetics. In this study, we focused on the kinetics of cytochrome P450 proteins (CYP450s) and the protein interior tunnel structure-dynamics relationship in terms of the substrate binding and leaving mechanism. A case in point is given by the prostaglandin H2 (PGH2) homologous isomerase of prostacyclin synthase. To calculate the reactant and product traversing the tunnels to and from the heme site, the free energy paths and tunnel potentials of mean force are constructed from steered molecular dynamics simulations and adaptive basing force umbrella sampling simulations. We explore the binding tunnels and critical residue lining characteristics for the ligand traverse and the underlying mechanism of CYP450 activity. Our theoretical analysis provides insights into the decisive role of the substrate tunnel binding process of the CYP450 mechanism and may be useful in drug design and protein engineering contexts.

Efficient Quantum-Chemical Calculations of Acid Dissociation Constants from Free-Energy Relationships.

The calculation of acid dissociation constants (pKa) is an important task in computational chemistry and chemoinformatics. Theoretically and with minimal empiricism, this is possible from computed acid dissociation free energies via so-called linear free-energy relationships. In this study some modifications are introduced to the latter, providing a straightforward, broadly applicable protocol with an adjustable degree of sophistication for quantum chemistry-based calculations of pKa in water. It targets a wide pKa range (∼70 units) and medium-sized, flexible molecules. Herein, a focus is set on the recently published r2SCAN-3c and related efficient composite density functionals and the semiempirical GFN2-xTB method, including a newly introduced energy correction for heterolytic dissociation, both in combination with implicit solvation models. The performance is evaluated in comparison with experimental data, showing mean errors often smaller than a targeted 1 pKa unit accuracy. Larger deviations are observed only upon inclusion of challenging highly negative (<-5) or positive (>15) pKa values. Among all those tested, it is found that B97-3c is the best performing functional, although rather independently of the density functional theory (DFT) method used; low root-mean-square errors of 0.8-1.0 pKa units for typical drugs are obtained. For optimal performance, it is recommended to employ DFT functional specific free-energy relationship parameters. Additionally, a significant conformational dependence of the pKa values is revealed and quantified for some nonrigid drug molecules.

Spontaneous Formation of an Fe/Mn Diamond Core: Models for the Fe/Mn Sites in Class 1c Ribonucleotide Reductases.

A handful of oxygen-activating enzymes has recently been found to contain Fe/Mn active sites, like Class 1c ribonucleotide reductases and R2-like ligand-binding oxidase, which are closely related to their better characterized diiron cousins. These enzymes are proposed to form high-valent intermediates with Fe-O-Mn cores. Herein, we report the first examples of synthetic Fe/Mn complexes that mimic doubly bridged intermediates proposed for enzymatic oxygen activation. Fe K-edge extended X-ray absorption fine structure (EXAFS) analysis has been used to characterize the structures of each of these compounds. Linear compounds accurately model the Fe···Mn distances found in Fe/Mn proteins in their resting states, and doubly bridged diamond core compounds accurately model the distances found in high-valent biological intermediates. Unlike their diiron analogues, the paramagnetic nature of Fe/Mn compounds can be analyzed by EPR, revealing S = 1/2 signals that reflect antiferromagnetic coupling between the high-spin Fe(III) and Mn(III) units of heterobimetallic centers. These compounds undergo electron transfer with various ferrocenes, linear compounds being capable of oxidizing diacetyl ferrocene, a weak reductant, and diamond core compounds being capable of oxidizing acetyl ferrocene. Diamond core compounds can also perform HAT reactions from substrates with X-H bonds with bond dissociation free energies (BDFEs) up to 75 kcal/mol and are capable of oxidizing TEMPO-H at rates of 0.32-0.37 M-1 s-1, which are comparable to those reported for some mononuclear FeIII-OH and MnIII-OH compounds. However, such reactivity is not observed for the corresponding diiron compounds, a difference that Nature may have taken advantage of in evolving enzymes with heterobimetallic active sites.

In silico modelling of apo-lactoferrin under simulated gastric conditions: Structural dynamics, binding with β-lactoglobulin and α-lactalbumin, and functional implications

This study employs computational techniques to investigate whether the inclusion of β-lactoglobulin and α-lactalbumin can enhance the molecular stability of apo-lactoferrin in conditions of gastric pH. Atomistic molecular dynamics simulations reveal that acidic pH results in weakened interactions between lactoferrin and the other proteins compared to those under neutral pH. Nevertheless, protein-protein dissociation free energy calculations using the umbrella sampling calculations confirm that some contacts are maintained between apo-lactoferrin and the other whey proteins, specifically the β-lactoglobulin units. This is manifested as a broad energy minimum at the intermediate inter-molecular distance of the inter-protein free energy profiles; thereby, demonstrating the formation of a nano-scale flocculant, followed by a potential gel, composed of protein particles. Practically, this property could be exploited to entrap further bioactive components within the protein matrix for novel engineered food materials. Furthermore, it was found that the anti-bacterial peptide regions of apo-lactoferrin are unaffected by the acidic pH, indicating the potential capability of apo-lactoferrin to act against harmful bacteria. Overall, this work unveils an understanding at a molecular level regarding the structural changes of the aforementioned proteins that maybe beneficial for future advancement of nutraceuticals.

Facile synthesis of MoS2/Ni2V3O8 nanosheets for pH-universal efficient hydrogen evolution catalysis

MoS2 presents an attractive performance for the hydrogen evolution reaction (HER) in acidic environment. However, its worse catalytic performance in neutral and alkaline media is problematic for practical application. Herein, stable MoS2/Ni2V3O8 nanosheets are synthesized by a facile hydrothermal method, which exhibit enhanced HER activities in all pH solutions as opposed to the pristine MoS2 and Ni2V3O8. The overpotentials are 48, 52, and 68 mV at 10 mA cm−2 with small Tafel slopes of 46, 54, and 55 mV dec−1 in alkaline, acidic and neutral media, respectively, which are competitive to that of Pt/C. The superior HER activity is due to the defective lattices, suitable interface band alignment, as well as the synergistic effect between MoS2 and Ni2V3O8. First-principles calculations show that the electronic coupling at the interface results in enhanced electronic conductivity, optimal hydrogen adsorption and water dissociation free energies. This work demonstrates that rational design of unique MoS2-based heterostructures can effectively improve their HER activities, which holds great potential for practical applications in pH-universal overall water splitting.

Solvent dependent C−H Bond Strength in a Nickel Pincer Complex

AbstractMetal coordination can substantially weaken the bond strength of X−H bonds in coordinated ligands. Despite the importance for redox catalysis, this phenomenon is surprisingly scarcely examined for C−H bonds of organometallic compounds. We here report a nickel(I) pincer complex with a remote methylene group in the ligand backbone that exhibits an unusually solvent dependent C−H bond dissociation free energy (BDFEC−H). Structural and thermochemical characterization in MeCN and THF indicates that the BDFEC−H strongly depends on solvent binding to the metal within the NiII/NiI redox couple.

Computer Simulations of the Dissociation Mechanism of Gleevec from Abl Kinase with Milestoning.

Gleevec (a.k.a., imatinib) is an important anticancer (e.g., chronic myeloid leukemia) chemotherapeutic drug due to its inhibitory interaction with the Abl kinase. Here, we use atomically detailed simulations within the Milestoning framework to study the molecular dissociation mechanism of Gleevec from Abl kinase. We compute the dissociation free energy profile, the mean first passage time for unbinding, and explore the transition state ensemble of conformations. The milestones form a multidimensional network with average connectivity of about 2.93, which is significantly higher than the connectivity for a one-dimensional reaction coordinate. The free energy barrier for Gleevec dissociation is estimated to be ∼10 kcal/mol, and the exit time is ∼55 ms. We examined the transition state conformations using both, the committor and transition function. We show that near the transition state the highly conserved salt bridge K217 and E286 is transiently broken. Together with the calculated free energy profile, these calculations can advance the understanding of the molecular interaction mechanisms between Gleevec and Abl kinase and play a role in future drug design and optimization studies.

Proton-Coupled Electron-Transfer Reactivity Controls Iron versus Sulfur Oxidation in Nonheme Iron-Thiolate Complexes.

Reaction of the five-coordinate FeII(N4S) complexes, [FeII(iPr3TACN)(abtX)](OTf) (abt = aminobenzenethiolate, X = H, CF3), with a one-electron oxidant and an appropriate base leads to net H atom loss, generating new FeIII(iminobenzenethiolate) complexes that were characterized by single-crystal X-ray diffraction (XRD), as well as UV-vis, EPR, and Mössbauer spectroscopies. The spectroscopic data indicate that the iminobenzenethiolate complexes have S = 3/2 ground states. In the absence of a base, oxidation of the FeII(abt) complexes leads to disulfide formation instead of oxidation at the metal center. Bracketing studies with separated proton-coupled electron-transfer (PCET) reagents show that the FeII(aminobenzenethiolate) and FeIII(iminobenzenethiolate) forms are readily interconvertible by H+/e- transfer and provide a measure of the bond dissociation free energy (BDFE) for the coordinated N-H bond between 64 and 69 kcal mol-1. This work shows that coordination to the iron center causes a dramatic weakening of the N-H bond and that Fe- versus S-oxidation in a nonheme iron complex can be controlled by the protonation state of an ancillary amino donor.

Insight Into Seeded Tau Fibril Growth From Molecular Dynamics Simulation of the Alzheimer's Disease Protofibril Core.

Aggregates of the microtubule associated tau protein are a major constituent of neurofibrillary lesions that define Alzheimer’s disease (AD) pathology. Increasing experimental evidence suggests that the spread of tau neurofibrillary tangles results from a prion-like seeding mechanism in which small oligomeric tau fibrils template the conversion of native, intrinsically disordered, tau proteins into their pathological form. By using atomistic molecular dynamics (MD) simulations, we investigate the stability and dissociation thermodynamics of high-resolution cryo-electron microscopy (cryo-EM) structures of both the AD paired-helical filament (PHF) and straight filament (SF). Non-equilibrium steered MD (SMD) center-of-mass pulling simulations are used to probe the stability of the protofibril structure and identify intermolecular contacts that must be broken before a single tau peptide can dissociate from the protofibril end. Using a combination of exploratory metadynamics and umbrella sampling, we investigate the complete dissociation pathway and compute a free energy profile for the dissociation of a single tau peptide from the fibril end. Different features of the free energy surface between the PHF and SF protofibril result from a different mechanism of tau unfolding. Comparison of wild-type tau PHF and post-translationally modified pSer356 tau shows that phosphorylation at this site changes the dissociation free energy surface of the terminal peptide. These results demonstrate how different protofibril morphologies template the folding of endogenous tau in distinct ways, and how post-translational modification can perturb the folding mechanism.

Exploring Ligand-Centered Hydride and H-Atom Transfer.

The nickel(II) complex [ON(H)O]Ni(PPh3) ([ON(H)O]2- = bis(3,5-di-tert-butyl-2-phenoxy)amine), bearing a protonated redox-active ligand, was examined for its ability to serve as a hydrogen atom (H•) and hydride (H-) donor. Deprotonation of [ON(H)O]Ni(PPh3) afforded the square-planar anion {[ONOcat]Ni(PPh3)}1-, whereas hydrogen atom transfer from [ON(H)O]Ni(PPh3) to TEMPO• in the presence of added PPh3 afforded five-coordinate [ONO]Ni(PPh3)2 that has been structurally characterized. In solution, this five-coordinate complex exists in equilibrium with four-coordinate [ONO]Ni(PPh3), and this ligand exchange equilibrium correlates with a valence tautomerization between the redox-active ligand and the nickel center. Abstraction of a hydride from [ON(H)O]Ni(PPh3) in the presence of PPh3 afforded the octahedral complex, [ONOq]Ni(OTf)(PPh3)2, which was characterized as an S = 1, nickel(II) complex. Bond dissociation free energy (BDFE) and hydricity (ΔG°H-) measurements benchmark the thermodynamic propensity of this complex to participate in ligand-centered H• and H- transfer reactions.

Quantum Chemical Modeling of the Effects of Hydrated Lime (Calcium Hydroxide) as a Filler in Bituminous Materials

Hydrated lime is widely used as a mineral filler to improve several properties of bituminous materials such as reducing the susceptibility of the composite to moisture-induced damage. Although experimental evidence supports the efficacy of using hydrated lime as a mineral filler, the molecular scale mechanism of reactivity of hydrated lime within the bitumen to reduce moisture damage is not understood. This is important when considering the durability of structural applications of bituminous materials such as asphalt concrete pavements subjected to both environmental and loading extremes. In this study, the interaction between hydrated lime and the key molecular building blocks of bitumen is modeled using density functional theory and compared against analogues of other common fillers such as calcite and quartz. Free energies of dissociation (ΔGdissoc) are calculated, and the nature of the bonds is characterized with contour maps of the Laplacian of the electron density. Hydrated lime is capable of reacting with specific functional groups in bitumen moieties and developing strong, water-resistant complexes. Among the functional groups investigated, carboxylic acids are the preferential reaction sites between hydrated lime and the bitumen moieties. Values as high as ΔGdissoc = +49.42 kcal/mol are reported for hydrated lime with water as the surrounding solvent. In contrast, analogues of calcite (ΔGdissoc = +15.84 kcal/mol) and quartz (ΔGdissoc = +4.76 kcal/mol) are unable to chemically react as strongly as hydrated lime in the presence of water. Contour maps of the Laplacian of the electron density indicate that the bonds between hydrated lime and model asphalt moieties are of an ionic nature. The atomistic modeling results correlate with thermodynamic calculations derived from experimental constants and are consistent with infrared spectrometric data.

Metal-Ion Influence on Ligand-Centered Hydrogen-Atom Transfer.

The ligand-centered hydrogen-atom-transfer (HAT) reactivity was examined for a family of group 10 metal complexes containing a tridentate pincer ligand derived from bis(2-mercapto-p-tolyl)amine, [SNS]H3. Six new metal complexes of palladium and platinum were synthesized with the [SNS] ligand platform in different redox and protonation states to complete the group 10 series previously reported with nickel. The HAT reactivity was examined for this family of nickel, palladium, and platinum complexes to determine the impact of a metal ion on the ligand-centered reactivity. Thermodynamic measurements revealed that N-H bond dissociation free energies increased by approximately 10 kcal mol-1 along the series Ni < Pd < Pt driven by changes to both the redox potential and pKa of the ligand. Kinetic analyses for all three metal complexes suggest that the barrier to the HAT reactivity is primarily entropic rather than enthalpic for this system.

Binding free energy of protein/ligand complexes calculated using dissociation Parallel Cascade Selection Molecular Dynamics and Markov state model.

We recently proposed a computational procedure to simulate the dissociation of protein/ligand complexes using the dissociation Parallel Cascade Selection Molecular Dynamics simulation (dPaCS-MD) method and to analyze the generated trajectories using the Markov state model (MSM). This procedure, called dPaCS-MD/MSM, enables calculation of the dissociation free energy profile and the standard binding free energy. To examine whether this method can reproduce experimentally determined binding free energies for a variety of systems, we used it to investigate the dissociation of three protein/ligand complexes: trypsin/benzamine, FKBP/FK506, and adenosine A2A receptor/T4E. First, dPaCS-MD generated multiple dissociation pathways within a reasonable computational time for all the complexes, although the complexes differed significantly in the size of the molecules and in intermolecular interactions. Subsequent MSM analyses produced free energy profiles for the dissociations, which provided insights into how each ligand dissociates from the protein. The standard binding free energies obtained by dPaCS-MD/MSM are in good agreement with experimental values for all the complexes. We conclude that dPaCS-MD/MSM can accurately calculate the binding free energies of these complexes.

Rational Preparation of Atomically Precise Non-Alkyl Tin-Oxo Clusters with Theoretical to Experimental Insights into Electrocatalytic CO 2 Reduction Applications

Tin oxides (SnO2) have been widely utilized in electronics, nanolithography, and catalysis. As the atomically precise models of SnO2, tin-oxo clusters (TOCs) not only provide opportunities for mech...

Generating Potent C–H PCET Donors: Ligand-Induced Fe-to-Ring Proton Migration from a Cp*FeIII–H Complex Demonstrates a Promising Strategy

Highly reactive organometallic species that mediate reductive proton-coupled electron transfer (PCET) reactions are an exciting area for development in catalysis, where a key objective focuses on tuning the reactivity of such species. This work pursues ligand-induced activation of a stable organometallic complex toward PCET reactivity. This is studied via the conversion of a prototypical Cp*FeIII-H species, [FeIII(η5-Cp*)(dppe)H]+ (Cp* = C5Me5-, dppe = 1,2-bis(diphenylphosphino)ethane), to a highly reactive, S = 1/2 ring-protonated endo-Cp*H-Fe relative, triggered by the addition of CO. Our assignment of the latter ring-protonated species contrasts with its previous reported formulation, which instead assigned it as a hypervalent 19-electron hydride, [FeIII(η5-Cp*)(dppe)(CO)H]+. Herein, pulse EPR spectroscopy (1,2H HYSCORE, ENDOR) and X-ray crystallography, with corresponding DFT studies, cement its assignment as the ring-protonated isomer, [FeI(endo-η4-Cp*H)(dppe)(CO)]+. A less sterically shielded and hence more reactive exo-isomer can be generated through oxidation of a stable Fe0(exo-η4-Cp*H)(dppe)(CO) precursor. Both endo- and exo-ring-protonated isomers are calculated to have an exceptionally low bond dissociation free energy (BDFEC-H ≈ 29 kcal mol-1 and 25 kcal mol-1, respectively) cf. BDFEFe-H of 56 kcal mol-1 for [FeIII(η5-Cp*)(dppe)H]+. These weak C-H bonds are shown to undergo proton-coupled electron transfer (PCET) to azobenzene to generate diphenylhydrazine and the corresponding closed-shell [FeII(η5-Cp*)(dppe)CO]+ byproduct.