Lysine-arginine advanced glycation end-product cross-links and the effect on collagen structure: A molecular dynamics study.

The accumulation of advanced glycation end-products is a fundamental process that is central to age-related decline in musculoskeletal tissues and locomotor system function and other collagen-rich tissues. However, although computational studies of advanced glycation end-product cross-links could be immensely valuable, this area remains largely unexplored given the limited availability of structural parameters for the derivation of force fields for Molecular Dynamics simulations. In this article, we present the bonded force constants, atomic partial charges and geometry of the arginine-lysine cross-links DOGDIC, GODIC, and MODIC. We have performed in vacuo Molecular Dynamics simulations to validate their implementation against quantum mechanical frequency calculations. A DOGDIC advanced glycation end-product cross-link was then inserted into a model collagen fibril to explore structural changes of collagen and dynamics in interstitial water. Unlike our previous studies of glucosepane, our findings suggest that intra-collagen DOGDIC cross-links furthers intra-collagen peptide hydrogen-bonding and does not promote the diffusion of water through the collagen triple helices.

Comparison of umbrella sampling and steered molecular dynamics methods for computing free energy profiles of aromatic substrates through phospholipid bilayers.

Understanding the permeation of molecules through lipid membranes is fundamental for predicting the cellular uptake of solutes and drug delivery mechanisms. In molecular simulations, the usual approach is to compute the free energy (FE) profile of a molecule across a model lipid bilayer, which can then be used to estimate the permeability of the molecule. Umbrella Sampling (US), which involves carrying out a series of biased simulations along a defined reaction coordinate (usually the bilayer normal direction), is a popular method for the computation of such FE profiles. However, US can be challenging to implement because the results are dependent on the strength of the biasing potential and the spacing of windows along the reaction coordinate, which, in practice, are usually optimized by an inefficient trial and error approach. The Steered Molecular Dynamics implementation of the Jarzynski Equality (JE-SMD) has been identified as an alternative to equilibrium sampling methods for measuring the FE change across a reaction coordinate. In the JE-SMD approach, equilibrium FE values are evaluated from the average of rapid non-equilibrium trajectories, thus avoiding the practical issues that come with US. Here, we use three different corrections of the JE-SMD method to calculate the FE change for the translocation of two aromatic substrates, phenylalanine and toluene, across a lipid bilayer and compare the accuracy and computational efficiency of these approaches to the results obtained using US. We show evidence that when computing the free energy profile, the JE-SMD approach suffers from insufficient sampling convergence of the bilayer environment and is dependent on the characteristic of the aromatic substrate itself. We deduce that, despite its drawbacks, US remains the more viable approach of the two for computing the FE profile.

The aggregation of striped nanoparticles in mixed phospholipid bilayers.

The unique and adjustable properties of nanoparticles present enormous opportunities for their use as targeted drug delivery vectors. For example, nanoparticles functionalized with key surface ligands have been shown to pass through phospholipid bilayers without causing localised disruption. However, the further effects nanoparticles have on multi-component phospholipid bilayers remain unclear. We use coarse-grained computational models to investigate the structural properties of mixed phospholipid bilayers in the presence of ligand-functionalized nanoparticles. Model bilayers are composed of DPPC, DUPC, DFPC and cholesterol, and the nanoparticles are striped with a hydrophobic-ligand band and charged-ligand spherical caps. Our results show that nanoparticles aggregate near unsaturated phospholipid regions, phospholipid bilayer phase-separation is promoted in the presence of nanoparticles, and the heterogeneous components of a phospholipid bilayer play a significant role in the lateral organization of nanoparticles. This study highlights the need for considering the complexity of realistic phospholipid bilayers when optimising ligand functionalized nanoparticles for efficient drug delivery vectors.

C-reactive protein concentrations are related to insulin resistance and metabolic syndrome as defined by the ATP III report.

BACKGROUND: C-reactive protein (CRP), very sensitive acute phase reactant, is an important marker of coronary artery disease. However, the relationship between insulin resistance and CRP has not been thoroughly studied. We observed the association between CRP, insulin resistance and metabolic syndrome as defined by the ATP III report, and thus identified the role of CRP in the relation to insulin resistance. METHODS: Seven hundred and sixty-seven subjects (436 men, 331 women) who underwent a medical check-up at health promotion center in a University Hospital during March 2002, aged 20-84 years, were included in this study. The components of metabolic syndrome as defined by the ATP III report and high sensitivity CRP levels were analyzed, and Homeostasis model assessment index (HOMA) and quantitative insulin sensitivity check index (QUICKI) were calculated. RESULTS: The mean concentrations of CRP in subjects according to the presence of 0, 1, 2, 3, 4, or 5 components of metabolic syndrome as defined by ATP III were 0.64, 0.95, 1.14, 1.19, 2.40, and 2.53 mg/l, respectively. The mean concentrations of CRP were significantly higher in subjects with a high insulin resistance (higher HOMA index and lower QUICKI) than in those with a low insulin resistance. Significant positive correlations were identified between CRP and BMI, waist circumference, triglyceride, blood pressure, glucose and HOMA index. A significant negative correlation was found between CRP and HDL cholesterol or QUICKI. CONCLUSION: These results suggest that metabolic syndrome and insulin resistance are associated with systemic inflammatory response, which plays an important pathogenic role in atherosclerosis.

Prevalence of the metabolic syndrome among 40,698 Korean metropolitan subjects.

INTRODUCTION: No published study has reported the prevalence of the metabolic syndrome in Asians using Adults Treatment Panel III (ATP III) criteria, comparing results with that using the obesity criteria of the Asia-Pacific region. METHODS: We evaluated the components of the metabolic syndrome among 40,698 participants aged 20-82 years (26,528 men; 14,170 women) who underwent a medical checkup at a University hospital in Seoul during 2001. RESULTS: Using ATP III criteria, the age-adjusted prevalence of the metabolic syndrome for Koreans was 6.8% in total (5.2% male, 9.0% female). Using the Asia-Pacific criteria for abdominal obesity based on waist circumference (APC-WC: >/=90 cm in men, >/=80 cm in women), prevalence rates were 10.9% (9.8% male, 12.4% female), and by the Asia-Pacific criteria for obesity based on body mass index (BMI) (APC-BMI: >/=25 kg/m2 in both sexes), rates were 13.1% (13.2% male, 13.1% female). Using BMI-adjusted logistic regression analysis, the odds ratio for the presence of the metabolic syndrome in those aged over 70 years against those aged 20-29 years was 13.8 (95% CI 8.2-23.2). Using age and BMI-adjusted logistic regression analysis, the odds ratio for the presence of the metabolic syndrome in women versus men was 1.4 (95% CI 1.2-1.5). The age-specific prevalence of the metabolic syndrome increased in both male and female participants, and females had higher prevalence rates than males in age groups older than 50 years. The highest prevalence rates were observed by applying APC-BMI criteria. CONCLUSION: Use of ATP III criteria to define the metabolic syndrome is not appropriate to Asian populations. The CVD risk attached to the use of the Asia-Pacific criteria needs to be determined in different Asian populations.