The photoexcitation of crystalline ice and amorphous solid water: A molecular dynamics study of outcomes at 11 K and 125 K.

Photoexcitation of crystalline ice Ih and amorphous solid water at 7-9 eV is examined using molecular dynamics simulations and a fully flexible water model. The probabilities of photofragment desorption, trapping, and recombination are examined for crystalline ice at 11 K and at 125 K and for amorphous solid water at 11 K. For 11 K crystalline ice, a fully rigid water model is also employed for comparison. The kinetic energy of desorbed H atoms and the distance travelled by trapped fragments are correlated to the location and the local environment of the photoexcited water molecule. In all cases, H atom desorption is found to be the most likely outcome in the top bilayer while trapping of all photofragments is most probable deeper in the solid where the likelihood for recombination of the fragments into H2O molecules also rises. Trajectory analysis indicates that the local hydrogen bonding network in amorphous solid water is more easily distorted by a photodissociation event compared to crystalline ice. Also, simulations indicate that desorption of OH radicals and H2O molecules are more probable in amorphous solid water. The kinetic energy distributions for desorbed H atoms show a peak at high energy in crystalline ice, arising from photoexcited water molecules in the top monolayer. This peak is less pronounced in amorphous solid water. H atoms that are trapped may be displaced by up to ∼10 water cages, but migrate on average 3 water cages. Trapped OH fragments tend to stay near the original solvent cage.

The docking of chiral analytes on proline-based chiral stationary phases: A molecular dynamics study of selectivity.

Molecular dynamics simulations are employed to examine the selectivity of four proline-based chiral stationary phases in two solvent environments, a relatively apolar n-hexane/2-propanol solvent and a polar water/methanol solvent. The four chiral surfaces are based on a BOC-terminated diproline, a TMA-terminated diproline, a TMA-terminated triproline and a TMA-terminated hexaproline. This range of chiral selectors allows an analysis of the impact of oligomer length and terminal group on selectivity while the two solvent environments indicate the impact of solvent hydrogen bonding and polarity. The selector-analyte interactions are examined for six closely related analytes that each have an aromatic moiety, a hydrogen, and an alcohol group directly bonded to the stereocenter. The analytes differ in the nature of the aromatic group (phenyl or anthracyl), in the attachment point (to the central ring or a side ring in the anthracyl), and in the fourth group bonded to the carbon (CH3, CF3, or C2H5). For each of the 48 solvent+selector+analyte systems, selectivity factors are calculated and, when possible, compared to experiment. The docking mode for these proline-based selectors is analyzed.

Poly-proline-based chiral stationary phases: a molecular dynamics study of triproline, tetraproline, pentaproline and hexaproline interfaces.

Poly-proline chains and derivatives have been recently examined as the basis for new chiral stationary phases in high performance liquid chromatography. The selectivity of poly-proline has been measured for peptides with up to ten proline units. In this article, we employ molecular dynamics simulations to examine the interfacial structure and solvation of surface-bound poly-proline chiral selectors. Specifically, we study the interfacial structure of trimethylacetyl-terminated poly-proline chains with three-to-six prolines. The surface includes silanol groups and end-caps, to better capture the characteristics of the stationary phase, and the solvent is either a polar water/methanol or a relatively apolar n-hexane/2-propanol mixture. We begin with a comprehensive ab initio study of the conformers, their energies, and an assessment of conformer flexibility. Force fields have been developed for each poly-proline selector. Molecular dynamics simulations are employed to study the preferred backbone conformations and solvent hydrogen bonding for different poly-proline/solvent interfaces. For triproline, the effect of two different terminal groups, trimethylacetyl and t-butyl carbamate are compared.

On simulations of complex interfaces: molecular dynamics simulations of stationary phases.

Methodological considerations for molecular dynamics simulations of complex interfaces are presented in this article. A slab geometry is examined in the context of stationary phases where selectivity occurs predominantly in pores within silica beads. Specifically, we examine the Whelk-O1 interface with n-hexane/2-propanol, the TMA-(Pro)(2)-N(CH(3))-tether interface with n-hexane/2-propanol, and the C(18)H(37)Si interface with water/methanol. The following methodological issues are considered in detail: The assessment of solvent density within the confined region and excluded volume of the interface; the structural equilibration of surface-bound moieties; solvent equilibration for binary mixtures; surface size effects, and periodic boundary conditions; the treatment of electrostatic interactions; and the impact of pore size.

Low serum creatinine levels as risk factor of diabetes mellitus: prediabetes considerations.

OBJECTIVE: It has been reported that low serum creatinine level is a risk factor of diabetes. We hypothesize that should this be true, serum creatinine levels would be lower and more prevalent in prediabetes than in normal individuals. MATERIALS AND METHODS: 1017 glucose tolerance tests performed at South West Pathology Service of the New South Wales Health, Australia, in 2008 were sorted into normal (control), prediabetes and diabetes based on decisive interpretation. All cases with creatinine results in the control (n=48), diabetes (n=18) and prediabetes (n=36) groups were selected. RESULTS: Mean levels of serum creatinine levels in the controls (80 +/- 32 micromol/L), diabetes (82 +/- 26 micromol/L) and prediabetes (82 +/- 23 micromol/L) were not statistically significantly different. The prevalence of low levels of serum creatinine is less in prediabetes (11%) than in the control (23%). CONCLUSION: Further studies using a larger number and adjusting for confounding factors is needed to ascertain the role of low serum creatinine level as a risk factor of diabetes.

Proline-based chiral stationary phases: a molecular dynamics study of the interfacial structure.

Proline chains have generated considerable interest as a possible basis for new selectors in chiral chromatography. In this article, we employ molecular dynamics simulations to examine the interfacial structure of two diproline chiral selectors, one with a terminal trimethylacetyl group and one with a terminal t-butyl carbamate group. The solvents consist of a relatively apolar n-hexane/2-propanol and a polar water/methanol mixture. We begin with electronic structure calculations for the two chiral selectors to assess the energetics of conformational changes, particularly along the backbone where the amide bonds can alternate between cis and trans conformations. Force fields have been developed for the two selectors, based on these ab initio calculations. Molecular dynamics simulations of the selective interfaces are performed to examine the preferred backbone conformations, as a function of end-group and solvent. The full chiral surface includes the diproline selectors, trimethylsilyl end-caps, and silanol groups. Connection is made with selectivity measurements on these interfaces, where significant differences are observed between these two very similar selectors.

Molecular dynamics simulations of the liquid-crystal phases of 2-(4-butyloxyphenyl)-5-octyloxypyrimidine and 5-(4-butyloxyphenyl)-2-octyloxypyrimidine.

In this paper, molecular dynamics simulations are employed to study the liquid-crystal phases of 2-(4-butyloxyphenyl)-5-octyloxypyrimidine and 5-(4-butyloxyphenyl)-2-octyloxypyrimidine. Both mesogens consist of aromatic phenyl-pyrimidine cores in between two identical alkoxy tails, but they differ in the preferred core conformation. The ab initio-based derivation of suitable molecular models is discussed in detail, with particular emphasis on capturing proper ring-ring interactions. The presence of ring quadrupoles in the molecular model is shown to be essential to the correct reproduction of the experimentally observed phases. Simulations of these fluids at various temperatures are performed and order, for the aromatic core and the flexible tails, is analyzed. To differentiate smectic- A from smectic- C phases, intermolecular structure is divided into contributions parallel and perpendicular to the director and layer normal.

Rational optimization of the Whelk-O1 chiral stationary phase using molecular dynamics simulations.

Rational in silico optimization of the Whelk-O1 chiral stationary phase (CSP) has been carried out based on the chiral recognition mechanism extracted from previous molecular dynamics simulations [C.F. Zhao, N.M. Cann, Anal. Chem. 80 (2008) 2426] of this CSP. Three modified CSPs have been examined. The first two are designed to increase selectivity by reducing the docking probability of the less retained analyte. The third modified selector reverses the amide bridge to introduce a structural motif found in the popular carbamate-derivatized polysaccharide CSPs [Y. Okamoto, M. Kawashima, K. Hatada, J. Am. Chem. Soc. 106 (1984) 5357]. For each modified selector, an atomistic model has been obtained through extensive ab initio calculations. The effect of selector modification is then evaluated via simulations of the modified interface in the presence of target analytes. Simulation results show that the separation factors are increased for the modified CSPs but in some cases elution orders are reversed. The Whelk-O1 CSP was originally designed to separate naproxen [W.H. Pirkle, C.J. Welch, B. LAmm, J. Org. Chem. 57 (1992) 3854]. With this in mind, molecular dynamics simulations of naproxen are compared for the original, and the modified, selectors.

A molecular dynamics study of chirality transfer from chiral surfaces to nearby solvent.

The presence of a chiral surface can alter the characteristics of nearby solvent molecules such that, on average, these molecules become chiral. The extent of this induced chirality and its dependence on the surface and solvent characteristics are explored in this article. Three surfaces employed in chiral chromatography are examined: The Whelk-O1 interface, a phenylglycine-derived chiral stationary phase (CSP), and a leucine-derived CSP. All three interfaces are "brush type" in that the chiral molecules are attached to the underlying substrate via an achiral tether. The solvents consist of ethanol, a binary n-hexane/ethanol solvent, 2-propanol, and a binary n-hexane/2-propanol solvent. Molecular dynamics simulations of the solvated chiral interfaces form the basis of the analysis. The chirality induced in the solvent is assessed based on a chirality index originally proposed by Osipov et al. [Mol. Phys. 84, 1193 (1995)]. Solvent chirality will depend on the solvent position relative to the surface. For this reason, a position-dependent chirality index is analyzed in detail.

Cardiovascular risk assessment in prediabetes: A hypothesis.

There are screening programs for future risk of cardiovascular disease (CVD) complications in diabetes, but not in subclinical diabetes. There is little or no risk and no differences between genders when a man or woman at age below 50 years presents blood pressure below 140/90 mmHg and total cholesterol/HDL less down 7.0. In the current screening programs, a hypothetical apparently non-diabetic and non-smoking person aged 49 years old; who present blood pressure 140/90 mmHg, fasting blood sugar 5.8 mmol/L and total cholesterol/HDL 6.5 has no risk of future CVD and does not require any intervention. However, by counting numbers, the person has two risk factors, hyperglycaemia and hyperlipidaemia. Furthermore, considering smoking as a factor and the propensity for hyperglycaemia-induced oxidative stress being a smoker-like effect of hyperglycaemia toxicity, the person actually has three risk factors, which qualifies the person for intervention. The issue is that a prediabetes sufferer is treated like a healthy person in the current screening programs. The problem here is that risk of CVD in prediabetes is inadequately assessed. We present a hypothesis that employs a combination of blood glucose level and an index of oxidative damage to improve CVD screening in prediabetes. We propose a longitudinal study to repeat the whole lipid modelling exercise in order to develop a separate model chart for the screening of future CVD in people with diagnosed or undiagnosed prediabetes. The proposal would also serve for people with undiagnosed diabetes.

A molecular dynamics study of chirality transfer: The impact of a chiral solute on an achiral solvent.

A solvation shell may adapt to the presence of a chiral solute by becoming chiral. The extent of this chirality transfer and its dependence on the solute and solvent characteristics are explored in this article. Molecular dynamics simulations of solvated chiral analytes form the basis of the analysis. The chirality induced in the solvent is assessed based on a series of related chirality indexes originally proposed by Osipov [M. A. Osipov et al., Mol. Phys. 84, 1193 (1995)]. Two solvents are considered: Ethanol and benzyl alcohol. Ethanol provides insight into chirality transfer when the solvent interacts with the solute primarily by a hydrogen bond. Several ethanol models have been considered starting with a nonpolarizable model, progressing to a fluctuating charge model, and finally, to a fully polarizable model. This progression provides some insights into the importance of solvent polarizability in the transfer of chirality. Benzyl alcohol, by virtue of the aromatic ring, increases the number of potential solvent-solute interactions. Thus, with these two solvents, the issue of compatibility between the solvent and solute is also considered. The solvation of three chiral solutes is examined: Styrene oxide, acenaphthenol, and n-(1-(4-bromophenyl)ethyl)pivalamide (PAMD). All three solutes have the possibility of hydrogen bonding with the solvent, the last two may also form ring-ring interactions, and the last also has multiple hydrogen bonding sites. For PAMD, the impact of conformational averaging is examined by comparing the chirality transfer about rigid and flexible solutes.

Molecular dynamics study of chiral recognition for the whelk-O1 chiral stationary phase.

In this article, we examine the docking of 10 analytes on the Whelk-O1 stationary phase. A proper representation of analyte flexibility is essential in the docking analysis, and analyte force fields have been developed from a series of B3LYP calculations. Molecular dynamics simulations of a representative Whelk-O1 interface, in the presence of racemic analyte and solvent, form the basis of the analysis of chiral selectivity. The most probable docking arrangements are identified, the energy changes upon docking are evaluated, and separation factors are predicted. From comparisons between the analytes, the mechanism of chiral selectivity is divided into contributions from hydrogen bonding, ring-ring interactions, steric hindrance, and molecular flexibility. We find that both hydrogen bonding and ring-ring interactions are necessary to localize the analyte within the Whelk-O1 cleft region. We also identify one docking mechanism that is often dominant and analyze the conditions that lead to alternate docking modes.

Polarizable and flexible model for ethanol.

A polarizable, flexible model for ethanol is obtained based on an extensive series of B3LYP/6-311++G(d,p) calculations and molecular dynamics simulations. The ethanol model includes electric-field dependence in both the atomic charges and the intramolecular degrees of freedom. Field-dependent intramolecular potentials have been attempted only once previously, for OH and HH stretches in water [P. Cicu et al., J. Chem. Phys. 112, 8267 (2000)]. The torsional potential involving the hydrogen-bonding hydrogen in ethanol is found to be particularly field sensitive. The methodology for developing field-dependent potentials can be readily generalized to other molecules and is discussed in detail. Molecular dynamics simulations of bulk ethanol are performed and the results are assessed based on comparisons with the self-diffusion coefficient [N. Karger et al., J. Chem. Phys. 93, 3437 (1990)], dielectric constant [J. T. Kindt and C. A. Schmuttenmaer, J. Phys. Chem. 100, 10373 (1996)], enthalpy of vaporization [R. C. Wilhoit and B. J. Zwolinski, J. Phys. Chem. Ref. Data, Suppl. 2, 2 (1973)], and experimental interatomic distributions [C. J. Benmore and Y. L. Loh, J. Chem. Phys. 112, 5877 (2000)]. The simultaneous variation of the atomic charges and the intramolecular potentials requires modified equations of motion and a multiple time step algorithm has been implemented to solve these equations. The article concludes with a discussion of the bulk structure and properties with an emphasis on the hydrogen bonding network.

The docking of chiral epoxides on the Whelk-O1 stationary phase: a molecular dynamics study.

The docking of analytes on the Whelk-O1 chiral stationary phase is explored for two chiral epoxides in a hexane solvent. Density functional theory calculations are employed to develop flexible models for R/S-styrene oxide (phenyl oxirane) and (R,R/S,S)-stilbene oxide (2,3-diphenyl oxirane). Molecular dynamics simulations of the racemates in the presence of the Whelk-O1 chiral stationary phase reveal the distribution of the enantiomers at the interface. The importance of hydrogen bonding and ring-ring interactions is explored along with an examination of the major docking arrangements. The interactions between the Whelk-O1 molecules and the chiral epoxide enantiomers are quite distinct and consistent with the experimental elution orders [S.E. Schaus, B.D. Brandes, J.F. Larrow, M. Tokunage, K.B. Hansen, A.E. Gould, M.E. Furrow, E.N. Jacobsen, J. Am. Chem. Soc. 124 (2001) 1307] and separation factors [W.H. Pirkle, C.J. Welch, Tetrahedron: Asymm. 5 (1994) 777]. The impact of a polar solvent modifier is examined for R/S-styrene oxide where selectivity in 80:20 n-hexane:2-propanol is assessed.

Solvation of the Whelk-O1 chiral stationary phase: a molecular dynamics study.

Density functional theory calculations and molecular dynamics simulations are employed to explore the solvation of the Whelk-O1 chiral stationary phase. First, a semi-flexible representation of the Whelk-O1 selective molecule is extracted from an extensive series of B3LYP/6-311+ G(2d,p) calculations. The resulting model is used to build a chiral surface, including end-caps, for molecular dynamics study of the interface between solvent and Whelk-O1. Three solvent environments in common use for Whelk-O1 HPLC have been examined: a normal-phase solvent of n-hexane/2-propanol; a reversed-phase solvent of water/methanol; and a supercritical solvent of CO(2) and methanol. In each case, we analyze the interface with an emphasis on solvent composition and solvent hydrogen bonding to the Whelk-O1 selector.

Discrimination in isotropic, nematic, and smectic phases of chiral calamitic molecules: a computer simulation study.

Racemic fluids of chiral calamitic molecules are investigated with molecular dynamics simulations. In particular, the phase behavior as a function of density is examined for eight racemates. The relationship between chiral discrimination and orientational order in the phase is explored. We find that the transition from the isotropic phase to a liquid crystal phase is accompanied by an increase in chiral discrimination, as measured by differences in radial distributions. Among ordered phases, discrimination is largest for smectic phases with a significant preference for heterochiral contact within the layers.

Evaluation of site-site bridge diagrams for molecular fluids.

The presence of bridge functions in formally exact integral equation theories is the primary obstacle preventing the extraction of exact fluid structure from these theories. The bridge functions are typically neglected but in many fluids their impact may be significant. Each bridge function can be subdivided into bridge diagrams, which are well defined but difficult to evaluate. The calculation of bridge diagrams for the Chandler-Silbey-Ladanyi (CSL) integral equation theory is the subject of this paper. In particular, we evaluate the diagrams required to yield an exact theory up to the first power in density [O(rho(1))] and provide algorithms that remain feasible for any molecule. Further, the bridge diagrams are evaluated and compared with the f-bond and h-bond formulations. Exact bridge diagrams are numerically evaluated for several chiral molecules, for two polar dimers, and for SPC/E water. The quality of the diagrams is assessed in two ways: First, the predicted interatomic distributions are compared with those obtained from Monte Carlo simulations. Second, the connectivity constraints are evaluated and the errors in satisfying these exact relationships are compared for the f-bond and h-bond formulations. For apolar fluids, a clear improvement in CSL theory is evident with the inclusion of O(rho(0)) and O(rho(1)) diagrams. In contrast, for polar fluids, the inclusion of bridge diagrams does not lead to improvement in the structural predictions.

The impact of the multipolar distribution on chiral discrimination in racemates.

This article explores the impact of the multipolar distribution on chiral discrimination in a series of racemic fluids. Discrimination is measured via the difference between the like-like (LL) and the like-unlike (LU) radial distributions in the liquid. We have found previously that the magnitude and orientation of the molecular dipole have a decisive impact on the short-ranged enantiomeric imbalance in racemates. Although quadrupolar and octupolar interactions decrease more rapidly with intermolecular separation, they can be significant at small separations, where enantiomeric imbalances occur. We have carefully selected a number of models in which we isolate the effects of the molecular quadrupole and octupole. We find that discrimination can be greatly enhanced by changes in the quadrupole moments. However, for octupole moments, changes in discrimination are small and some octupoles inhibit discrimination. We identify the quadrupole moment closest to the plane perpendicular to the direction of the molecular dipole as the moment that has the greatest favorable effect on chiral discrimination in racemates. In racemates where this moment is large, we have found differences of up to 40% between the LL and the LU radial distributions.

Evidence for the involvement of DNA-dependent protein kinase in the phenomena of low dose hyper-radiosensitivity and increased radioresistance.

PURPOSE: To investigate the role of DNA-dependent protein kinase (DNA-PK) in the phenomena of low dose hyper-radiosensitivity (HRS) and increased radioresistance (IRR) using the genetically related M059 cell lines of disparate PRKDC status. MATERIALS AND METHODS: Clonogenic survival was measured for the three cell lines following low doses of X-irradiation using a flowactivated cell sorting (FACS) plating technique. The presence of PRKDC, G22p1 and Xrcc5 proteins was determined by Western blotting and a kinase assay used to measure DNA-PK complex activity. RESULTS: The survival responses for the three cell lines over the 0-0.3Gy dose range were comparable, but differences in radiosensitivity were evident at doses >0.4Gy. M059K and M059J/Fus1 cells (both PRKDC competent) exhibited marked HRS/IRR responses, albeit to different extents. M059J cells (PRKDC incompetent) were extremely radiosensitive exhibiting a linear survival curve with no evidence of IRR. The presence of IRR was coincident with the presence of PRKDC protein and functional DNA-PK activity. CONCLUSIONS: HRS is a response that is independent of DNA-PK activity. In contrast, IRR showed a dependence on the presence of PRKDC protein and functional DNA-PK activity. These data support a role for DNA-PK activity in the IRR response.