Alzheimer's disease is a debilitating neurodegenerative disorder associated with the abnormal self-assembly of amyloid-beta (Abeta) peptides into fibrillar species. N-methylated peptides homologous to the central hydrophobic core of the Abeta peptide are potent inhibitors of this aggregation process. In this work, we use fully atomistic molecular dynamics simulations to study the interactions of the N-methylated peptide inhibitor Abeta16-20m (Ac-Lys(16)-(Me)Leu(17)-Val(18)-(Me)Phe(19)-Phe(20)-NH(2)) with a model protofilament consisting of Alzheimer Abeta16-22 peptides. Our simulations indicate that the inhibitor peptide can bind to the protofilament at four different sites: 1), at the edge of the protofilament; 2), on the exposed face of a protofilament layer; 3), between the protofilament layers; and 4), between the protofilament strands. The different binding scenarios suggest several mechanisms of fibrillogenesis inhibition: 1), fibril inhibition of longitudinal growth (in the direction of monomer deposition); 2), fibril inhibition of lateral growth (in the direction of protofilament assembly); and 3), fibril disassembly by strand removal and perturbation of the periodicity of the protofilament (disruption of fibril morphology). Our simulations suggest that the Abeta16-20m inhibitor can act on both prefibrillar species and mature fibers and that the specific mechanism of inhibition may depend on the structural nature of the Abeta aggregate. Disassembly of the fibril can be explained by a mechanism through which the inhibitor peptides bind to disaggregated or otherwise free Abeta16-22 peptides in solution, leading to a shift in the equilibrium from a fibrillar state to one dominated by inhibitor-bound Abeta16-22 peptides.

Proton conducting oxide ceramics have shown potential for use in fuel cell technologies. Understanding the energy pathways for proton conduction could help us design more efficient fuel cell materials. This paper describes how octahedral tilting affects the relative energies of proton binding sites, transition states, and conduction pathways in cubic and pseudo-cubic perovskites. First, the structure for cubic and pseudo-cubic forms of BaTiO(3), BaZrO(3), CaTiO(3), and CaZrO(3), is found. Even when cubic symmetry is enforced, CaTiO(3), and CaZrO(3) exhibit octahedral tilting distortions characteristic of orthorhombic phases while BaTiO(3) and BaZrO(3) remain undistorted. Octahedral tilting gives rise to proton binding sites facilitating inter- and intra-octahedral proton transfer while the proton binding sites of undistorted perovskites facilitate only intra-octahedral proton transfer. The nudged elastic band method is used to find minimum energy paths between the proton binding sites. As distortions increase, inter-octahedral proton transfer barriers decrease while intra-octahedral proton transfer barriers increase. Concurrently, rotational barriers from oxygens facilitating inter-octahedral proton transfer increase while rotational barriers from oxygens facilitating intra-octahedral proton transfer decrease. Intra-octahedral transfer is the rate-limiting step to the lowest energy extended proton conduction pathway in all the perovskites considered.

102 80 182 53* 41* 94 Southend 65 67 132 18 12 30 Total 167 147 314 71* 53* 124 _~~~~~_~_ *One male and two female patients were not traced. One female died between the home visit and the hospital appointement-that is, social follow-up: 70 men, 51 women interviewed; medical follow-up: 70 men, 50 women interviewed.

The Zori 1.0 package for electronic structure computations is described. Zori performs variational and diffusion Monte Carlo computations as well as correlated wave function optimization. This article presents an overview of the implemented methods and code capabilities.

We study the effects of confinement, sequence frustration, and surface interactions on the thermodynamics of dimerization of an off-lattice minimalist beta-barrel protein using replica exchange molecular dynamics. We vary the degree of frustration of the protein by tuning the specificity of the hydrophobic interactions and investigate dimerization in confining spheres of different radii. We also investigate surface effects by tethering the first residue of one of the proteins to a uniformly repulsive surface. We find that increasing the confinement and frustration stabilize the dimer, while adding a repulsive surface decreases its stability. Different ensembles of structures, including properly dimerized and various partially dimerized states, are observed at the association transition temperature T(a), depending on the amount of frustration and whether a surface is present. The presence of a surface is predicted to alter the morphology of larger aggregates formed from partially unfolded dimeric conformations.