Protein conformational diseases, including Alzheimer's, Huntington's, and Parkinson's diseases, result from protein misfolding, giving a distinct fibrillar feature termed amyloid. Recent studies show that only the globular (not fibrillar) conformation of amyloid proteins is sufficient to induce cellular pathophysiology. However, the 3D structural conformations of these globular structures, a key missing link in designing effective prevention and treatment, remain undefined as of yet. By using atomic force microscopy, circular dichroism, gel electrophoresis, and electrophysiological recordings, we show here that an array of amyloid molecules, including amyloid-beta(1-40), alpha-synuclein, ABri, ADan, serum amyloid A, and amylin undergo supramolecular conformational change. In reconstituted membranes, they form morphologically compatible ion-channel-like structures and elicit single ion-channel currents. These ion channels would destabilize cellular ionic homeostasis and hence induce cell pathophysiology and degeneration in amyloid diseases.

This paper briefly reviews the current status of the most popular methods for combined quantum mechanical/molecular mechanical (QM/MM) calculations, including their advantages and disadvantages. There is a special emphasis on very general link-atom methods and various ways to treat the charge near the boundary. Mechanical and electric embedding are contrasted. We consider methods applicable to gas-phase organic chemistry, liquid-phase organic and organometallic chemistry, biochemistry, and solid-state chemistry. Then we review some recent tests of QM/MM methods and summarize what we learn about QM/MM from these studies. We also discuss some available software. Finally, we present a few comments about future directions of research in this exciting area, where we focus on more intimate blends of QM with MM.

Amyloid beta protein (AbetaP) is the major constituent of senile plaques associated with Alzheimer's disease (AD). However, its mechanistic role in AD pathogenesis is poorly understood. Globular and nonfibrillar AbetaPs are continuously released during normal metabolism. Using techniques of atomic force microscopy, laser confocal microscopy, electrical recording, and biochemical assays, we have examined the molecular conformations of reconstituted globular AbetaPs as well as their real-time and acute effects on neuritic degeneration. Atomic force microscopy (AFM) of AbetaP1-42 shows globular structures that do not form fibers in physiological-buffered solution for up to 8 h of continuous imaging. AFM of AbetaP1-42 reconstituted in a planar lipid bilayer reveals multimeric channel-like structures. Consistent with these AFM resolved channel-like structures, biochemical analysis demonstrates that predominantly monomeric AbetaPs in solution form stable tetramers and hexamers after incorporation into lipid membranes. Electrophysiological recordings demonstrate the presence of multiple single channel currents of different sizes. At the cellular level, AbetaP1-42 allows calcium uptake and induces neuritic abnormality in a dose- and time-dependent fashion. At physiological nanomolar concentrations, rapid neuritic degeneration was observed within minutes; at micromolar concentrations, neuronal death was observed within 3-4 h. These effects are prevented by zinc (an AbetaP channel blocker) and by the removal of extracellular calcium, but are not prevented by antagonists of putative AbetaP cell surface receptors. Thus, AbetaP channels may provide a direct pathway for calcium-dependent AbetaP toxicity in AD.

The primary oxidant of cytochrome P450 enzymes, Compound I, is hard to detect experimentally; in the case of cytochrome P450(cam), this intermediate does not accumulate in solution during the catalytic cycle even at temperatures as low as 200 K (ref 4). Theory can play an important role in characterizing such elusive species. We present here combined quantum mechanical/molecular mechanical (QM/MM) calculations of Compound I of cytochrome P450(cam) in the full enzyme environment as well as density functional studies of the isolated QM region. The calculations assign the ground state of the species, quantify the effect of polarization and hydrogen bonding on its properties, and show that the protein environment and its specific hydrogen bonding to the cysteinate ligand are crucial for sustaining the Fe-S bond and for preventing the full oxidation of the sulfur.

The stereospecific cytochrome P450-catalyzed hydroxylation of the C(5)-H((5-exo)) bond in camphor has been studied theoretically by a combined quantum mechanical/molecular mechanical (QM/MM) approach. Density functional theory is employed to treat the electronic structure of the active site (40-100 atoms), while the protein and solvent environment (ca. 24,000 atoms) is described by the CHARMM force field. The calculated energy profile of the hydrogen-abstraction oxygen-rebound mechanism indicates that the reaction takes place in two spin states (doublet and quartet), as has been suggested earlier on the basis of calculations on simpler models ("two-state reactivity"). While the reaction on the doublet potential energy surface is nonsynchronous, yet effectively concerted, the quartet pathway is truly stepwise, including formation of a distinct intermediate substrate radical and a hydroxo-iron complex. Comparative calculations in the gas phase demonstrate the effect of the protein environment on the geometry and relative stability of intermediates (in terms of spin states and redox electromers) through steric constraints and electronic polarization.

The two-dimensional (2D) superconducting state is a fragile state of matter susceptible to quantum phase fluctuations. Although superconductivity has been observed in ultrathin metal films down to a few layers 1-10 , it is still not known whether a single layer of ordered metal atoms, which represents the ultimate 2D limit of a crystalline film, could be superconducting. Here we report scanning tunnelling microscopy measurements on single atomic layers of Pb and In grown epitaxially on Si(111) substrate, and demonstrate unambiguously that superconductivity does exist at such a 2D extreme. The film shows a superconducting transition temperature of 1.83 K for an atom areal density n = 10.44 Pb atoms nm −2 , 1.52 K for n = 9.40 Pb atoms nm −2 and 3.18 K for n = 9.40 In atoms nm −2 , respectively. We confirm the occurrence of superconductivity by the presence of superconducting vortices under magnetic field. In situ angle-resolved photoemission spectroscopy measurements reveal that the observed superconductivity is due to the interplay between the Pb-Pb (In-In) metallic and the Pb-Si (In-Si) covalent bondings.The one-atomic-layer films of Pb and In studied here were grown with atomic precision on bulk-terminated Si(111) substrate using molecular beam epitaxy. The one-atomic-layer films of Pb have two different structural phases depending on the coverage (for sample preparation, see the Methods section). Figure 1a,d shows the schematic structure and scanning tunnelling microscopy (STM) topograph of the so-called striped incommensurate (SIC) phase, which has a Pb coverage of 4/3 monolayers (ML;. Here 1 ML is defined as the surface atomic density of the Si(111) with areal density n = 7.84 atoms nm −2 . In a unit cell of the SIC-Pb phase, there are four Pb atoms per three surface Si atoms. Three of the four Pb atoms each form a covalent bond with an underlying Si atom, leaving one Pb atom without bonding to the Si substrate. Besides the covalent bonds with the Si substrate, the metal atoms also form metallic bonds within the metal overlayer. As all Pb atoms are located exactly in the same atomic-layer sheet (see the large-scale STM image and cross-section height profiles in Supplementary Fig. S1), the resulting areal density of Pb atoms is 10.44 nm −2 . Compared with the bulk Pb(111) plane, the lattice of the SIC phase is compressed by 5%.Ultralow-temperature (down to 0.40 K) scanning tunnelling spectroscopy (STS) on the SIC phase reveals a clear signature of superconductivity. Figure 2a shows the tunnelling spectra taken on the SIC phase using a superconducting Nb tip. At 0.42 K,

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

In many applications of multilevel/multiscale methods, an active zone must be modeled by a high-level electronic structure method, while a larger environmental zone can be safely modeled by a lower-level electronic structure method, molecular mechanics, or an analytic potential energy function. In some cases though, the active zone must be redefined as a function of simulation time. Examples include a reactive moiety diffusing through a liquid or solid, a dislocation propagating through a material, or solvent molecules in a second coordination sphere (which is environmental) exchanging with solvent molecules in an active first coordination shell. In this article, we present a procedure for combining the levels smoothly and efficiently in such systems in which atoms or groups of atoms move between high-level and low-level zones. The method dynamically partitions the system into the high-level and low-level zones and, unlike previous algorithms, removes all discontinuities in the potential energy and force whenever atoms or groups of atoms cross boundaries and change zones. The new adaptive partitioning (AP) method is compared to Rode's "hot spot" method and Morokuma's "ONIOM-XS" method that were designed for multilevel molecular dynamics (MD) simulations. MD simulations in the microcanonical ensemble show that the AP method conserves both total energy and momentum, while the ONIOM-XS method fails to conserve total energy and the hot spot method fails to conserve both total energy and momentum. Two versions of the AP method are presented, one scaling as O(2N) and one with linear scaling in N, where N is the number of groups in a buffer zone separating the active high-level zone from the environmental low-level zone. The AP method is also extended to systems with multiple high-level zones to allow, for example, the study of ions and counterions in solution using the multilevel approach.