Copper is a redox-active metal with many important biological roles. Consequently, its distribution and oxidation state are subject to stringent regulation. A large body of clinicopathological, circumstantial, and epidemiological evidence suggests that the dysregulation of copper is intimately involved in the pathogenesis of Alzheimer's disease. Other light transition metals such as iron and zinc may affect copper regulation by competing for copper binding sites and transporters. Therapeutic interventions targeting the regulation of copper are promising, but large gaps in our understanding of copper biochemistry, amyloidogenesis, and the nature of oxidative stress in the brain must be addressed.

Family B heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) play important roles in carbohydrate metabolism. Recent structures of family B GPCR-Gs protein complexes reveal a disruption in the α-helix of transmembrane segment 6 (TM6) not observed in family A GPCRs. To investigate the functional impact of this structural difference, we compared the structure and function of the glucagon receptor (GCGR; family B) with the β2 adrenergic receptor (β2AR; family A). We determined the structure of the GCGR-Gs complex by means of cryo–electron microscopy at 3.1-angstrom resolution. This structure shows the distinct break in TM6. Guanosine triphosphate (GTP) turnover, guanosine diphosphate release, GTP binding, and G protein dissociation studies revealed much slower rates for G protein activation by the GCGR compared with the β2AR. Fluorescence and double electron-electron resonance studies suggest that this difference is due to the inability of agonist alone to induce a detectable outward movement of the cytoplasmic end of TM6.

Reverse micelles (RMs) made from water and sodium bis(2-ethylhexyl) sulfosuccinate (AOT) are commonly studied experimentally as models of aqueous microenvironments. They are small enough for individual RMs to also be studied by molecular dynamics (MD) simulation, which yields detailed insight into their structure and properties. Although RM size is determined by the water loading ratio (i.e. the molar ratio of water to AOT), experimental measurements of RM size are imprecise and inconsistent, which is problematic when seeking to understand the relationship between water loading ratio and RM size, and when designing models for study by MD simulation. Therefore, a systematic study of RM size was performed by MD simulation with the aims of determining the size of an RM for a given water loading ratio, and of reconciling the results with experimental measurements. Results for a water loading ratio of 7.5 indicate that the interaction energy between AOT anions and other system components is at a minimum when there are 62 AOT anions in each RM. The minimum is due to a combination of attractive and repulsive electrostatic interactions that vary with RM size and the dielectric effect of available water. Overall, the results agree with a detailed analysis of previously published experimental data over a wide range of water loading ratios, and help reconcile seemingly discrepant experimental results. In addition, water loss and gain from an RM is observed and the mechanism of water exchange is outlined. This kind of RM model, which faithfully reproduces experimental results, is essential for reliable insights into the properties of RM-encapsulated materials.

Alzheimer's disease is the most common form of dementia. It is a neurodegenerative and incurable disease that is associated with the tight packing of amyloid fibrils. This packing is facilitated by the compatibility of the ridges and grooves on the amyloid surface. The GxMxG motif is the major factor creating the compatibility between two amyloid surfaces, making it an important target for the design of amyloid aggregation inhibitors. In this study, a peptide, experimentally proven to bind Aβ40 fibrils at the GxMxG motif, was mutated by a novel methodology that systematically replaces amino acids with residues that share similar chemical characteristics and subsequently assesses the energetic favorability of these mutations by docking. Successive mutations are combined and reassessed via docking to a desired level of refinement. This methodology is both fast and efficient in providing potential inhibitors. Its efficiency lies in the fact that it does not perform all possible combinations of mutations, therefore decreasing the computational time drastically. The binding free energies of the experimentally studied reference peptide and its three top scoring derivatives were evaluated as a final assessment/valuation. The potential of mean forces (PMFs) were calculated by applying the Jarzynski‚s equality to results of steered molecular dynamics simulations. For all of the top scoring derivatives, the PMFs showed higher binding free energies than the reference peptide substantiating the usage of the introduced methodology to drug design.

Previously published experimental studies have suggested that when the 40-residue amyloid beta peptide is encapsulated in a reverse micelle, it folds into a structure that may nucleate amyloid fibril formation (Yeung, P. S.-W.; Axelsen, P. H. J. Am. Chem. Soc. 2012, 134, 6061 ). The factors that induce the formation of this structure have now been identified in a multi-microsecond simulation of the same reverse micelle system that was studied experimentally. Key features of the polypeptide-micelle interaction include the anchoring of a hydrophobic residue cluster into gaps in the reverse micelle surface, the formation of a beta turn at the anchor point that brings N- and C-terminal segments of the polypeptide into proximity, high ionic strength that promotes intramolecular hydrogen bond formation, and deformation of the reverse micelle surface to facilitate interactions with the surface along the entire length of the polypeptide. Together, these features cause the simulation-derived vibrational spectrum to red shift in a manner that reproduces the red-shift previously reported experimentally. On the basis of these findings, a new mechanism is proposed whereby membranes nucleate fibril formation and facilitate the in-register alignment of polypeptide strands that is characteristic of amyloid fibrils.