Molecular dynamics simulations to gain insights into the stability and morphologies of K3 oligomers from beta2-microglobulin.

beta2-Microglobulin (beta2-m) forms amyloid fibrils in patients undergoing long-term hemodialysis. K3 peptide, a Ser20-Lys41 fragment of beta2-m, has been known to form fibrils over a wide range of pH and solvent conditions. Recent solid-state NMR has revealed that K3 oligomer adopts a parallel U-shaped beta-strand-turn-beta-strand motif. In order to investigate the stability and morphologies of K3 oligomers with different sizes (dimer, trimer, and tetramer) and organizations (single and double layers), several all-atom molecular dynamics simulations were conducted at 310 K and pH 2 in water and 2,2,2-trifluoroethanol (TFE). For single-layered organizations, our results show that TFE destabilizes the stacking of K3 peptides due to the fact that TFE weakens the intermolecular hydrophobic interactions of K3 oligomers. In addition, we also identified that the loop region is stabilized by the hydrophobic cluster involving resides Y7, F11, and I16. Our results further suggest that K3 tetramer is a potential minimal nucleus seed for the formation of K3 protofibrils. For double-layered organizations in water, our data demonstrate that K3 peptides can form various stable assemblies through different interfacial arrangements, such as NN, NC, and CC, by different driving forces. We further propose that the stacking of different interfaces between two facing beta-sheets of K3 peptides could be related to different fibril morphologies, which is in good agreement with the previous experimental results, showing that K3 protofibrils associated to formed mature fibrils with a wide range of diameters from 4 to 15 nm when they were transferred from 20% (v/v) TFE to aqueous solution.

RING domains functioning as E3 ligases reveal distinct structural features: a molecular dynamics simulation study.

RING domain, a cysteine-rich motif that chelates two zinc ions, has been shown to regulate many biological processes such as mediating a crucial step in the ubiquitinylation pathway. In order to investigate the distinct structural features for the RING domains functioning as E3 ligases, several molecular dynamics simulations involving the c-Cbl, CNOT4 (with E3 ligase function), and p44 (no E3 ligase function) RING domains were conducted in this study. Our results reveal that the structural stability of the recognition site is a basic requirement for the RING domains functioning as E3 ligases. The structural stability of the recognition site is maintained by the hydrophobic core and hydrogen bonding network. Another important structural feature of the RING domains functioning as E3 ligases is the stable distances between the recognition site and the zinc ion binding sites S1 and S2. Moreover, the RING domains functioning as E3 ligases seem to exhibit lower beta stability due to the higher proportion of proline residues in their sequences. However, no significant difference of the other secondary (alpha and turn) and the tertiary structural stabilities can be observed among these three RING domains.

The potential role of phagocytic capacity in the osteolytic process induced by polyethylene wear particles.

Osteolysis induced by ultra-high molecular weight polyethylene wear particles is the major cause of long-term failure of artificial joints. We examined the effects of wear particles on bioactivity by analysing the biophysical aspects of particle phagocytosis. We estimated the maximum number of internalized particles (the phagocytic capacity) for particles of various sizes and shapes. We demonstrated that elongated particles had a smaller phagocytic capacity than spherical particles of the same volume. A review of the literature showed that the ratio of particle concentration (number of particles/number of cells) to phagocytic capacity is critical for particle-induced biological responses. When this ratio was < 1, the biological response was approximately proportional to the ratio itself. When this ratio was > 1, limited changes in the biological response were observed. The saturation level of the phagocytic capacity for a particle population appears to reflect the degree of polyethylene particle-induced biological response.

Polycyclic aromatic hydrocarbons inhibit the activity of acetylcholinesterase purified from electric eel.

Polycyclic aromatic hydrocarbons (PAHs) are formed during the incomplete combustion of fossil fuels, wood and municipal waste incineration, from internal combustion engines, and from various food cooking operations and are common environmental contaminants which have been detected in surface waters, sediments, soils, plants, and both rural and urban air. In this study, we have shown that, for the first time, in vitro addition of PAHs dose-dependently inhibited the activity of acetylcholinesterase purified from electric eel in a competitive manner. The PAHs containing 3 or higher aromatic rings showed the highest inhibitory effect with the IC50 values between 2 and 6 ppm. Among the PAHs tested, chrysene and pyrene exhibit the highest and lowest potency with IC50 values of 2. 40+/-0.04 and 5.22+/-0.38 ppm, respectively. PAHs with lower number of aromatic rings, such as naphthalene, acenaphthylene and fluorene, and oxygenated PAHs, such as anthraquinone and xanthone, showed no or slight inhibition of the acetylcholinesterase activity.