Search

This study considers a scheme for sampling phase space in large molecules based on Car−Parrinello ab initio molecular dynamics. The scheme makes use of a combined quantum mechanics and molecular mechanics (QM/MM) method augmented with a multiple-time-step technique. This scheme makes it possible to oversample the computationally less expensive MM region relative to the QM domain. The goal here is to provide better ensemble averaging in the MM region that is usually larger in size and therefore typically has a higher degree of configurational variability. It is shown that the multiple-time-step integrator will generate the same trajectory as a standard molecular dynamics integrator. Moreover, with a gradual rescaling of masses, the energy conservation of a multiple-time-step simulation can be satisfied to the same extent as a standard simulation. Finally, it is demonstrated that the multiple-time-step QM/MM method can accelerate the equilibration and configurational sampling of a molecular dynamics simulation as it is used in thermodynamic integration. The scheme is not intended as a tool for generating trajectories in actual dynamics.

Car−Parrinello molecular dynamics simulations have been performed to investigate the solvation effects on the prototype SN2 reaction between Cl^- and CH3Cl. The free energy barrier for this reaction in water was calculated using constrained dynamics at a constant temperature of 300 K and constant volume. Calculations on the isolated system (reaction in the gas phase at zero temperature) were performed for reference purposes. Qualitatively, the calculations confirm that the double-well free energy profile of the reaction in the gas phase is converted into a single barrier by solvation and that the height of the barrier increases significantly. Quantitatively, there are two error sources. At the electronic structure side, the Becke−Perdew functional underestimates the barrier height by 8 kcal/mol. At the dynamics side, there is a “hysteresis” effect&sbd;too slow an adaptation of the solvent structure to changes in the reaction coordinate&sbd;yielding an estimated error of 3 kcal/mol in the free energy barrier height. After correction for these errors, the calculated value of the free energy barrier is 27 kcal/mol. Considering the accuracy of the solvent−solvent and solvent−reactant interactions of ca. 1 kcal/mol, this compares very well with the experimental estimate of 26.6 kcal/mol. This indicates that the ab initio (DFT) MD very well captures the differential energetic as well as entropic effects of the solvation when going from the (solvated) reactants to the initial ion−dipole complex to the transition state.

A combination of quantum mechanics and molecular mechanics QM/MM has been used to study the capture of ethylene by Brookhart's Ni diimine catalysts of the type (ArN&dbd;C(R‘)−C(R‘)&dbd;NAr)Ni^II−propyl⁺ with (1) R‘ = H and Ar = H, (2) R‘ = H and Ar = 2,6-C6H3(i-Pr)2, or (3) R‘ = CH3 and Ar = 2,6-C6H3(i-Pr)2. The study made use of both conventional “static” density functional theory (DFT) based calculations as well as slow growth first principle molecular dynamics (FPMD) DFT methods to examine the capture of ethylene. Examination of the static potential energy surface of all three catalyst models 1, 2, and 3 reveals that there is no enthalpic barrier to the capture process. However, both the static and molecular dynamics simulations suggest that there is an entropic barrier to the association that originates from the loss of rotational and translational entropies upon association. The FPMD QM/MM slow growth barriers were calculated to be 7.5, 10.3, and 10.8 kcal/mol at 300 K for catalysts 1, 2, and 3, respectively. An analysis suggests that the trend in the barriers can be related to the size of the active site. The free energy barrier for the pure QM model of 1 has also been estimated from a series of frequency calculations. This approach provides a barrier of 7.7 kcal/mol (and 6.8 kcal/mol without quantum dynamical contributions), which is in fair agreement with the 7.5 kcal/mol barrier (without quantum dynamical contributions) calculated from the slow growth simulations. Analysis of the estimate from the frequency calculations suggests that this barrier estimate represents an upper limit, since the components of the vibrational entropy that compensate the loss of rotational and translational entropy upon association are partially neglected in the treatment.

The aim of this study was to evaluate the renal protective effect of linotroban, a thromboxane A2 receptor antagonist, in 25 patients with malignant tumours scheduled for cisplatin therapy. Cisplatin was administered 1 h after the start of a 24-h continuous infusion of linotroban or placebo. Glomerular filtration rate and effective renal plasma flow were measured. Infusions of cisplatin decreased glomerular filtration rate by 17 ± 25 mL min-1 (P = 0.049 vs. baseline) and effective renal plasma flow by 94 ± 150 mL min-1 (P = 0.049 vs. baseline) in the placebo group. In the linotroban group a decrease in glomerular filtration rate by 11 ± 18 mL min-1 (P = 0.050 vs. baseline) and in effective renal plasma flow by 26 ± 63 mL min-1 (P = 0.2 vs. baseline) was noted. However, no difference was noted between groups in response to treatment. Our findings indicate that linotroban may not be useful for prevention of cisplatin's acute nephrotoxic effects.

We test a new implementation of the combined quantum mechanics and molecular mechanics (QM/MM) methodology applied within the Car−Parrinello framework to perform ab initio molecular dynamics simulations of extended systems. The novel method is applied to determine the free energy barrier of the chain termination process in a nickel diimine based ethylene polymerization catalyst of the type (ArN&dbd;C(R)−C(R)&dbd;NAr)Ni(II)−R‘⁺, where R = Me and Ar = 2,6-C6H3(i-Pr)2. In this combined QM/MM ab initio molecular dynamics simulation, the Ni diimine core was treated at the Becke88−Perdew86 DFT level while the large substituted aryl rings were treated by the AMBER molecular mechanics force field. A 39 000 time step slow growth simulation of the termination process at 300 K has been performed providing a free energy barrier of ΔF^&thermod; = 14.8 kcal/mol by thermodynamic integration. This is in excellent agreement with the experimental termination barrier of ΔG^&thermod; ≈ 16 kcal/mol. Without the bulky ligands, the analogous pure QM simulation provided a free energy barrier of ΔF^&thermod; = 9.8 kcal/mol.

We present a comprehensive survey of chain termination and long chain branching processes for the “constrained-geometry” olefin polymerization catalyst (CpSiH2NH)Ti-R⁺ (R = ethyl, propyl) based on static and dynamic density functional theory. Car-Parrinello molecular dynamics calculations are used to locate reaction pathways and estimate free energies of activation, and conventional static calculations are used to ascertain stationary points and relative energies. We have examined three distinct chain termination processes:  (a) β-hydrogen transfer to the monomer, (b) β-hydrogen transfer to the metal, and (c) olefin C−H σ-bond metathesis. We find alternative (a) to be the most viable one [ΔH^&thermod;el(R = ethyl) = 32 kJ/mol; ΔF^&thermod;(R = ethyl) = 40.1; ΔF^&thermod;(R = propyl) = 43 ± 8 kJ/mol at 300 K], whereas pathways (b) [ΔH^&thermod;el(R = propyl) = 67; ΔF^&thermod;(R = propyl) = 57 ± 3 at 300 K] and (c) [ΔH^&thermod;el(R = ethyl) = 93; ΔF^&thermod;(R = ethyl) = 91.7 kJ/mol; ΔF^&thermod;(R = propyl) = 87 ± 5 at 300 K] have much higher activation barriers. In addition, we investigated an unconventional long chain branching mechanism (d), where a polymer chain binds to the metal center in an η²-agostic fashion via aliphatic hydrogens, followed by activation of one aliphatic C−H bond and transfer of the hydrogen to the α-carbon (σ-bond metathesis). For this process we have found a large electronic barrier of ΔH^&thermod;el(R = ethyl) = 77 kJ/mol and a free energy barrier of ΔF^&thermod;(R = ethyl) = 72.3 kJ/mol; ΔF^&thermod;(R = propyl) = 70 ± 3 kJ/mol at 300 K. On the basis of our data, we favor the conventional long chain branching mechanism consisting of chain termination via mechanism (a) to produce a vinyl-terminated chain and reincorporation of the terminated chain into the polymer. In this study we have calculated free energy barriers for each of the aforementioned processes by a conventional static calculations and by a Car-Parrinello “first principles” molecular dynamics simulations. The agreement of the two methods is exceptional, demonstrating utility of first principles molecular dynamics to determine free energy barriers.

Site selectivity for nucleophilic attack of a π-allyl−Pd(II) complex with a bidentate phosphine−pyrazole ligand by an amine has been investigated with first-principles density functional calculations using the projector augmented wave method. The interplay between steric and electronic effects, namely the trans influence, is elucidated. While the trans influence favors nucleophilic attack at the carbon in a pseudo-trans position to the phosphine, site selectivity is dominated by steric effects between the allyl group and a groove in the catalyst surface, which prescribe an orientation of the allyl out of the P−Pd−N plane. The direction of this out-of-plane orientation determines the site of nucleophilic attack for a given isomer of the allyl complex, irrespective of whether this site is cis or trans to the phosphine. Our results provide insight into the observed relation between isomeric distributions of the allyl complexes and the resulting selectivities.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.