A classical force field has been developed in order to investigate the selective exchange of oxyanions (TcO4– vs SO42–) with other ligands (H2O, Cl–) to an aqueous Fe3+–ethylenediamine (EDA) complex. Potentials of mean force for a range of exchange reactions were generated using umbrella sampling and classical molecular dynamics simulations in order to calculate the affinity of each oxyanion for the Fe3+–EDA complex in aqueous solution. In order to accurately introduce a degree of specificity for the interaction of Fe3+ with each ligand type, force field parameters were tuned to match the results of density functional theory calculations. Preferential exchange of H2O, Cl–, and SO42– for TcO4– via an interchange mechanism is observed, in agreement with experimental observations. Both the relative solvation entropies and enthalpies of the anions were found to be critically important factors governing the magnitude of the observed selectivities. These results have important implications for the design and modeling of functionalized materials for the remediation of land contaminated with radioactive 99Tc.

Adsorption of actinyl ions onto mineral surfaces is one of the main mechanisms that control the migration of these ions in environmental systems. Here, we present computational classical molecular dynamics (MD) simulations to investigate the behavior of U(VI) in contact with different calcite surfaces. The calcium-uranyl-carbonate [Ca2UO2(CO3)3] species is shown to display both inner- and outer-sphere adsorption to the flat {101̅4} and the stepped {314̅8} and {31̅2̅16} planes of calcite. Free energy calculations, using the umbrella sampling method, are employed to simulate adsorption paths of the same uranyl species on the different calcite surfaces under aqueous condition. Outer-sphere adsorption is found to dominate over inner-sphere adsorption because of the high free energy barrier of removing a uranyl–carbonate interaction and replacing it with a new uranyl–surface interaction. An important binding mode is proposed involving a single vicinal water monolayer between the surface and the sorbed complex. From the free energy profiles of the different calcite surfaces, the uranyl complex was also found to adsorb preferentially on the acute-stepped {314̅8} face of calcite, in agreement with experiment.

Carbonate anion exchange reactions with water in the uranyl-carbonate and calcium-uranyl-carbonate aqueous systems have been investigated using computational methods. Classical molecular dynamics (MD) simulations with the umbrella sampling technique were employed to determine potentials of mean force for the exchange reactions of water and carbonate. The presence of calcium counter-ions is predicted to increase the stability of the uranyl-carbonate species in accordance with previous experimental observations. However, the free energy barrier to carbonate exchange with water is found to be comparable both in the presence and absence of calcium cations. Possible implications of these results for uranyl adsorption on mineral surfaces are discussed. Density functional theory (DFT) calculations were also used to confirm the trends observed in classical molecular dynamics simulations and to corroborate the validity of the potential parameters employed in the MD scheme.

The binding of a selection of competitive imidazo [1,2-b] pyridazine inhibitors of PIM-1 kinase with nanomolar activity has been analyzed using computational methods. Molecular dynamics simulations using umbrella sampling to determine a potential of mean force have been used to accurately predict the relative free energies of binding of these inhibitors, from −4.3 to −9.5 kcal mol−1, in excellent agreement with the trends observed in previous experimental assays. The relative activity of the inhibitors could not be accounted for by any single effect or interaction within the active site and could only be fully reproduced when the overall free energies were considered, including important contributions from interactions outside the hinge region and using explicit solvent in the active site. The potential of mean force for the displacement of the glycine-rich phosphate binding loop (P-loop) has also been estimated and shown to be an important feature in the binding of these ligands.

The effect of benzene fluorination on C–H⋯π interactions is studied using a number of computational methods applied to a range of intermolecular complexes. High level wavefunction methods (CCSD(T)) predict a slightly greater interaction energy for complexes of benzene with methane or fucose, compared to corresponding complexes involving hexafluorobenzene. A number of more approximate treatments, DFT with the M06-2X functional, PM3-D* and MM methods, give interaction energies within 1 kcal mol−1 of the high level values, and also correctly predict that the interaction energy is slightly greater for benzene compared to hexafluorobenzene. However, the DFT-D model used here predicts that the interaction energy is slightly greater for hexafluorobenzene. Molecular dynamics simulations, employing the GLYCAM-06 force field, validated here, are used to model the complexes of benzene and hexafluorobenzene with β-cyclodextrin in aqueous solution. We predict the binding free energies of the complexes to be within 0.5 kcal mol−1, and suggest that the different chemical shifts of the H5 protons observed in the two complexes arise from their slightly different structures, rather than from different binding energies.

Proton transfer reactions are the rate-limiting steps in many biological and synthetic chemical processes, often requiring complex cofactors or catalysts to overcome the generally unfavourable thermodynamic process of carbanion intermediate formation. It has been suggested that quantum tunnelling processes enhance the kinetics of some of these reactions, which when coupled to protein motions may be an important consideration for enzyme catalysis. To obtain a better fundamental and quantitative understanding of these proton transfer mechanisms, a computational analysis of the intramolecular proton transfer from a carbon acid in the small molecule, 4-nitropentanoic acid, in aqueous solution is presented. Potential-energy surfaces from gas-phase, implicit and QM/MM (quantum mechanical/molecular mechanical) explicit solvation quantum chemistry models are compared, and the potential of mean force, for the full reaction coordinate, using umbrella-sampling molecular dynamics is analysed. Semi-classical multidimensional tunnelling corrections are also used to estimate the quantum tunnelling contributions and to understand the origin of the primary deuterium kinetic isotope effects (KIEs). The computational results are found to be in excellent agreement with the KIEs and the energetics obtained experimentally.

Many metallabenzene complexes appear to exhibit an enhanced thermodynamic stability which has been attributed to the concept of aromaticity. Analysis of the ring currents induced by a magnetic field, either by direct visualization or by considering nuclear or nucleus-independent chemical shielding values (NMR or NICS), have become useful theoretical tools to characterize the aromaticity of many molecules involving the main group elements. We have analyzed 21 metallabenzenes using variations of these techniques, which take account of the large core and metal orbital contributions which often lead to transition-metal-containing systems exhibiting anomalous shielding values. Analysis of individual orbital contributions to both the ring currents and chemical shielding values based upon the ipsocentric and CSGT (continuous set of gauge transformations) methods has shown that complexes such as the 18 electron Ir or Rh(C5H5)(PH3)2Cl2 molecules should be classed as aromatic, whereas the 16 electron complexes such as Os or Ru(C5H5)(PH3)2Cl2 should not, despite having the same occupancy of π-MOs. The differences can be directly attributed to the HOMO/LUMO b2 in-plane (dxy) molecular orbital, which, when unoccupied, is available to disrupt the delocalized currents typical of aromatic systems. A range of Pd and Pt metallabenzenes with cyclopentadienyl and phosphine ligands is also discussed as having aromatic and nonaromatic character, respectively.

Carbonate anion exchange reactions with water in the uranyl-carbonate and calcium-uranyl-carbonate aqueous systems have been investigated using computational methods. Classical molecular dynamics (MD) simulations with the umbrella sampling technique were employed to determine potentials of mean force for the exchange reactions of water and carbonate. The presence of calcium counter-ions is predicted to increase the stability of the uranyl-carbonate species in accordance with previous experimental observations. However, the free energy barrier to carbonate exchange with water is found to be comparable both in the presence and absence of calcium cations. Possible implications of these results for uranyl adsorption on mineral surfaces are discussed. Density functional theory (DFT) calculations were also used to confirm the trends observed in classical molecular dynamics simulations and to corroborate the validity of the potential parameters employed in the MD scheme.

Proton transfer reactions are the rate-limiting steps in many biological and synthetic chemical processes, often requiring complex cofactors or catalysts to overcome the generally unfavourable thermodynamic process of carbanion intermediate formation. It has been suggested that quantum tunnelling processes enhance the kinetics of some of these reactions, which when coupled to protein motions may be an important consideration for enzyme catalysis. To obtain a better fundamental and quantitative understanding of these proton transfer mechanisms, a computational analysis of the intramolecular proton transfer from a carbon acid in the small molecule, 4-nitropentanoic acid, in aqueous solution is presented. Potential-energy surfaces from gas-phase, implicit and QM/MM (quantum mechanical/molecular mechanical) explicit solvation quantum chemistry models are compared, and the potential of mean force, for the full reaction coordinate, using umbrella-sampling molecular dynamics is analysed. Semi-classical multidimensional tunnelling corrections are also used to estimate the quantum tunnelling contributions and to understand the origin of the primary deuterium kinetic isotope effects (KIEs). The computational results are found to be in excellent agreement with the KIEs and the energetics obtained experimentally.

The effect of benzene fluorination on C–H⋯π interactions is studied using a number of computational methods applied to a range of intermolecular complexes. High level wavefunction methods (CCSD(T)) predict a slightly greater interaction energy for complexes of benzene with methane or fucose, compared to corresponding complexes involving hexafluorobenzene. A number of more approximate treatments, DFT with the M06-2X functional, PM3-D* and MM methods, give interaction energies within 1 kcal mol−1 of the high level values, and also correctly predict that the interaction energy is slightly greater for benzene compared to hexafluorobenzene. However, the DFT-D model used here predicts that the interaction energy is slightly greater for hexafluorobenzene. Molecular dynamics simulations, employing the GLYCAM-06 force field, validated here, are used to model the complexes of benzene and hexafluorobenzene with β-cyclodextrin in aqueous solution. We predict the binding free energies of the complexes to be within 0.5 kcal mol−1, and suggest that the different chemical shifts of the H5 protons observed in the two complexes arise from their slightly different structures, rather than from different binding energies.