Bond breaking in epoxy systems: A combined QM/MM approach.

A novel method to combine quantum mechanics (QM) and molecular mechanics has been developed to accurately and efficiently account for covalent bond breaking in polymer systems under high strain without the use of predetermined break locations. Use of this method will provide a better fundamental understanding of the mechano-chemical origins of fracture in thermosets. Since classical force fields cannot accurately account for bond breaking, and QM is too demanding to simulate large systems, a hybrid approach is required. In the method presented here, strain is applied to the system using a classical force field, and all bond lengths are monitored. When a bond is stretched past a threshold value, a zone surrounding the bond is used in a QM energy minimization to determine which, if any, bonds break. The QM results are then used to reconstitute the system to continue the classical simulation at progressively larger strain until another QM calculation is triggered. In this way, a QM calculation is only computed when and where needed, allowing for efficient simulations. A robust QM method for energy minimization has been determined, as well as appropriate values for the QM zone size and the threshold bond length. Compute times do not differ dramatically from classical molecular mechanical simulations.

Computation of the binding free energy of peptides to graphene in explicit water.

The characteristic properties of graphene make it useful in an assortment of applications. One particular application--the use of graphene in biosensors--requires a thorough understanding of graphene-peptide interactions. In this study, the binding of glycine (G) capped amino acid residues (termed GXG tripeptides) to trilayer graphene surfaces in aqueous solution was examined and compared to results previously obtained for peptide binding to single-layer free-standing graphene [A. N. Camden, S. A. Barr, and R. J. Berry, J. Phys. Chem. B 117, 10691-10697 (2013)]. In order to understand the interactions between the peptides and the surface, binding enthalpy and free energy values were calculated for each GXG system, where X cycled through the typical 20 amino acids. When the GXG tripeptides were bound to the surface, distinct conformations were observed, each with a different binding enthalpy. Analysis of the binding energy showed the binding of peptides to trilayer graphene was dominated by van der Waals interactions, unlike the free-standing graphene systems, where the binding was predominantly electrostatic in nature. These results demonstrate the utility of computational materials science in the mechanistic explanation of surface-biomolecule interactions which could be applied to a wide range of systems.

Binding of solvated peptide (EPLQLKM) with a graphene sheet via simulated coarse-grained approach.

Binding of a solvated peptide A1 ((1)E (2)P (3)L (4)Q (5)L (6)K (7)M) with a graphene sheet is studied by a coarse-grained computer simulation involving input from three independent simulated interaction potentials in hierarchy. A number of local and global physical quantities such as energy, mobility, and binding profiles and radius of gyration of peptides are examined as a function of temperature (T). Quantitative differences (e.g., the extent of binding within a temperature range) and qualitative similarities are observed in results from three simulated potentials. Differences in variations of both local and global physical quantities suggest a need for such analysis with multiple inputs in assessing the reliability of both quantitative and qualitative observations. While all three potentials indicate binding at low T and unbinding at high T, the extent of binding of peptide with the temperature differs. Unlike un-solvated peptides (with little variation in binding among residues), solvation accentuates the differences in residue binding. As a result the binding of solvated peptide at low temperatures is found to be anchored by three residues, (1)E, (4)Q, and (6)K (different from that with the un-solvated peptide). Binding to unbinding transition can be described by the variation of the transverse (with respect to graphene sheet) component of the radius of gyration of the peptide (a potential order parameter) as a function of temperature.

Ginseng and anticancer drug combination to improve cancer chemotherapy: a critical review.

Ginseng, a well-known herb, is often used in combination with anticancer drugs to enhance chemotherapy. Its wide usage as well as many documentations are often cited to support its clinical benefit of such combination therapy. However the literature based on objective evidence to make such recommendation is still lacking. The present review critically evaluated relevant studies reported in English and Chinese literature on such combination. Based on our review, we found good evidence from in vitro and in vivo animal studies showing enhanced antitumor effect when ginseng is used in combination with some anticancer drugs. However, there is insufficient clinical evidence of such benefit as very few clinical studies are available. Future research should focus on clinically relevant studies of such combination to validate the utility of ginseng in cancer.

Simulations of peptide-graphene interactions in explicit water.

The interaction of graphene with biomolecules has a variety of useful applications. In particular, graphitic surfaces decorated with peptides are being considered for high performance biochemical sensors. The interaction of peptides with graphene can also provide insight into the binding behavior of larger biomolecules. In this investigation, we have computed the binding enthalpies of a series of GXG tripeptides with graphene using classical molecular dynamics. Explicit water molecules were included to capture the effect of solvent. Of the twenty amino acid residues examined (X in GXG), arginine, glutamine, and asparagine exhibit the strongest interactions with graphene. Analysis of the trajectories shows that the presence of graphene affects the peptide conformation relative to its conformation in solution. We also find that the peptides favor the graphene interface predominantly due to the influence of the solvent, with hydrophilic residues binding more strongly than hydrophobic residues. These results demonstrate the need to include explicit solvent atoms when modeling peptide-graphene systems to mimic experimental conditions. Furthermore, the scheme outlined herein may be widely applicable for the determination and validation of surface interaction parameters for a host of molecular fragments using a variety of techniques, ranging from coarse-grained models to quantum mechanical methods.

Rejection-free Monte Carlo scheme for anisotropic particles.

We extend the geometric cluster algorithm [J. Liu and E. Luijten, Phys. Rev. Lett. 92, 035504 (2004)], a highly efficient, rejection-free Monte Carlo scheme for fluids and colloidal suspensions, to the case of anisotropic particles. This is made possible by adopting hyperspherical boundary conditions. A detailed derivation of the algorithm is presented, along with extensive implementation details as well as benchmark results. We describe how the quaternion notation is particularly suitable for the four-dimensional geometric operations employed in the algorithm. We present results for asymmetric Lennard-Jones dimers and for the Yukawa one-component plasma in hyperspherical geometry. The efficiency gain that can be achieved compared to conventional, Metropolis-type Monte Carlo simulations is investigated for rod-sphere mixtures as a function of rod aspect ratio, rod-sphere diameter ratio, and rod concentration. The effect of curved geometry on physical properties is addressed.

Interactions between charged surfaces with ionizable sites.

A key factor controlling the interactions between surfaces in aqueous solutions is the surface charge density. Surfaces typically become charged though a titration process where surface groups can become ionized based on their dissociation constant and the pH of the solution. In this work, we use a Monte Carlo method to treat this process in a system with two planar surfaces with explicitly described ionizable sites in a salt solution. We focus on a system with a surface density of ionizable sites set to 4.8 nm(-2), corresponding to silica. We find that the surface charge density changes as the surfaces come close to contact due to interactions between the ionizable groups on each surface. In addition, we observe an attraction between the surfaces above a threshold surface charge, in good agreement with previous theoretical predictions based on uniformly charged surfaces. However, close to contact we find the force is significantly different than for the uniformly charged case.

Modulation of novel cardiorenal and inflammatory biomarkers by intravenous nitroglycerin and nesiritide in acute decompensated heart failure: an exploratory study.

BACKGROUND: Modulation of novel cardiorenal and inflammatory markers may provide insight into the disease process and outcomes of patients with acute decompensated heart failure. METHODS AND RESULTS: In this open-labeled, prospective, randomized study, 89 patients received either nesiritide (NES) or nitroglycerin (NTG) infusion by standard protocol. The serum or plasma concentrations of cystatin-C and inflammatory markers (high-sensitivity C-reactive protein, tumor necrosis factor-α, transforming growth factor-ß1, and interleukin-6) were measured in 66 patients with acute decompensated heart failure at baseline and during drug infusion. Mean baseline values for demographics were not significantly different between NTG and NES groups; however, baseline inflammatory markers were elevated on admission. In NES compared with NTG groups, lower cystatin-C (1449 versus 2739 ng/mL, P<0.05) and IL-6 (25 versus 50 pg/mL, P<0.05) were observed. There were no significant differences in concentrations of high-sensitivity C-reactive protein, tumor necrosis factor-α, and transforming growth factor-ß1 between groups over time. CONCLUSIONS: The differential modulation effects of cystatin-C and interleukin-6 but not other inflammatory markers, in response to NES compared with NTG therapy, may provide important implications for vasodilator therapy. Further studies are warranted to confirm these findings. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842023.

Renal function and neurohormonal changes following intravenous infusions of nitroglycerin versus nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Rises in serum creatinine and efficacy have been reported as dose-related effects of nesiritide and nitroglycerin in acute decompensated heart failure (ADHF). However, no study has evaluated the comparative safety, efficacy, and biomarkers of optimally dosed nesiritide versus nitroglycerin in ADHF. METHODS AND RESULTS: Eighty-nine ADHF patients were prospectively randomized to receive either nesiritide (0.01 µg kg(-1) min(-1) ± bolus) or nitroglycerin (maximally tolerated doses by standard protocol). Blood urea nitrogen (BUN), and creatinine were obtained during 48 hours of intravenous infusion. B-Type natriuretic peptide (BNP) and N-terminal (NT) proBNP concentrations were measured during hospitalization. There were no significant differences in BUN, serum creatinine, creatinine clearance, or hospitalization and mortality. Although concentrations of BNP and NT-proBNP were significantly decreased over time, the comparative reductions between the 2 vasodilators were similar. CONCLUSIONS: Nesiritide and nitroglycerin produce similar hemodynamic effects, do not worsen markers of renal function, and produce significant, yet similar, reductions in neurohormones over time. Both nitroglycerin at maximally titrated doses and nesiritide at standard doses are safe and effective in patients with ADHF who require vasodilator therapy.

Effective interactions in mixtures of silica microspheres and polystyrene nanoparticles.

We investigate the effect of small concentrations of highly charged nanoparticles on the stability of uncharged colloidal microspheres using large-scale simulations. Employing pair potentials that accurately represent mixtures of silica microspheres and polystyrene nanoparticles as studied experimentally, we are able to demonstrate that nanoparticle-induced stabilization can arise from a relatively weak van der Waals attraction between the colloids and nanoparticles. This demonstrates that the nanoparticle haloing mechanism for colloidal stabilization is of considerable generality and potentially can be applied to large classes of systems. The range of optimal nanoparticle concentrations can be tuned by controlling the attraction between colloids and nanoparticles.

Thyroid hormone regulates endogenous amyloid-beta precursor protein gene expression and processing in both in vitro and in vivo models.

Thyroid hormone negatively regulates the amyloid-beta precursor protein (APP) gene in thyroid hormone receptor (TR)-transfected neuroblastoma cells. A negative thyroid hormone response element (nTRE) that mediates this regulation has been identified in the first exon of the APP gene. We demonstrate in an in vivo system that expression of APP mRNA, APP protein, and APP secretase cleavage products in mouse brain is influenced by thyroid status. Adult female mice were made hyperthyroid or hypothyroid for 3 weeks and compared to euthyroid mice. APP gene product expression was increased in hypothyroid mouse brain and reduced in hyperthyroid mouse brain, when compared to euthyroid controls. We observed similar effects of thyroid hormone on endogenous APP gene expression in human neuroblastoma cells. The incidence of hypothyroidism increases with age, and localized hypothyroidism of central nervous system has been reported in some patients with Alzheimer's disease (AD). Reduced action of thyroid hormone on the APP gene may contribute to AD pathology by increasing APP expression and the levels of processed APP products. These findings may be an underlying mechanism contributing to the association of hypothyroidism with AD in the elderly, as well as identifying a potential therapeutic target. Pharmacologic supplementation of thyroid hormone, or its analogs, may reduce APP gene expression and beta amyloid peptide accumulation.

Complexity of small silicon self-interstitial defects.

The combination of long-time, tight-binding molecular dynamics and real-time multiresolution analysis techniques reveals the complexity of small silicon interstitial defects. The stability of identified structures is confirmed by ab initio relaxations. The majority of structures were previously unknown, demonstrating the effectiveness of the approach. A new, spatially extended tri-interstitial ground state structure is identified as a probable nucleation site for larger extended defects and may be key for the compact-to-extended transition.