Computational design of a protein crystal Lanci, Christopher J; MacDermaid, Christopher M; Kang, Seung-gu ...
Proceedings of the National Academy of Sciences - PNAS,
05/2012, Letnik:
109, Številka:
19
Journal Article
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Protein crystals have catalytic and materials applications and are central to efforts in structural biology and therapeutic development. Designing predetermined crystal structures can be subtle given ...the complexity of proteins and the noncovalent interactions that govern crystallization. De novo protein design provides an approach to engineer highly complex nanoscale molecular structures, and often the positions of atoms can be programmed with sub-Å precision. Herein, a computational approach is presented for the design of proteins that self-assemble in three dimensions to yield macroscopic crystals. A three-helix coiled-coil protein is designed de novo to form a polar, layered, three-dimensional crystal having the P6 space group, which has a "honeycomb-like" structure and hexameric channels that span the crystal. The approach involves: (i) creating an ensemble of crystalline structures consistent with the targeted symmetry; (ii) characterizing this ensemble to identify "designable" structures from minima in the sequence-structure energy landscape and designing sequences for these structures; (iii) experimentally characterizing candidate proteins. A 2.1 Å resolution X-ray crystal structure of one such designed protein exhibits sub-Å agreement backbone root mean square deviation (rmsd) with the computational model of the crystal. This approach to crystal design has potential applications to the de novo design of nanostructured materials and to the modification of natural proteins to facilitate X-ray crystallographic analysis.
Magnetic multilayers offer diverse opportunities for the development of ultrafast functional devices through advanced interface and layer engineering. Nevertheless, a method for determining their ...dynamic properties as a function of depth throughout such stacks has remained elusive. By probing the ferromagnetic resonance modes with element-selective soft x-ray resonant reflectivity, we gain access to the magnetization dynamics as a function of depth. Most notably, using reflectometry ferromagnetic resonance, we find a phase lag between the coupled ferromagnetic layers in CoFeB/MgO/Ta4 multilayers that is invisible to other techniques. The use of reflectometry ferromagnetic resonance enables the time-resolved and depth-resolved probing of the complex magnetization dynamics of a wide range of functional magnetic heterostructures with absorption edges in the soft x-ray wavelength regime.
In order to improve the bonding between hydroxyapatite (HAP) particles and poly(
l-lactide) (PLLA), and hence to increase mechanical properties of the PLLA/HAP composite as potential bone substitute ...material, the HAP nano-particles were surface-grafted with PLLA and further blended with PLLA. The structure and properties of the composites were subsequently investigated by the mechanical property testing, the differential scanning calorimeter measurements (DSC), the scanning electron microscopy (SEM), the polarized optical microscopy (POM), and the cell culture. The PLLA molecules grafted on the HAP surfaces, as inter-tying molecules, played an important role in improving the adhesive strength between the particles and the polymer matrix. At a low content (∼4
wt%) of surface grafted-HAP (g-HAP), the PLLA/g-HAP nano-composites exhibited higher bending strength and impact energy than the pristine PLLA, and at a higher g-HAP content (e.g., 20
wt%), the modulus was remarkably increased. It implied that PLLA could be strengthened as well as toughened by g-HAP nano-particles. The results of biocompatibility test showed that the g-HAP existing in the PLLA composite facilitated both adhesion and proliferation of chondrocytes on the PLLA/g-HAP composite film.
A search for mixing between active neutrinos and light sterile neutrinos has been performed by looking for muon neutrino disappearance in two detectors at baselines of 1.04 and 735 km, using a ...combined MINOS and MINOS+ exposure of 16.36×10^{20} protons on target. A simultaneous fit to the charged-current muon neutrino and neutral-current neutrino energy spectra in the two detectors yields no evidence for sterile neutrino mixing using a 3+1 model. The most stringent limit to date is set on the mixing parameter sin^{2}θ_{24} for most values of the sterile neutrino mass splitting Δm_{41}^{2}>10^{-4} eV^{2}.
Hec1 (highly expressed in cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators, and phosphorylation of Hec1 S165 by ...Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here we showed that new derivatives of INH (inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394-408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408-422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application.
Complex-oxide materials exhibit physical properties that involve the interplay of charge and spin degrees of freedom. However, an ambipolar oxide that is able to exhibit both electron-doped and ...hole-doped ferromagnetism in the same material has proved elusive. Here we report ambipolar ferromagnetism in LaMnO
, with electron-hole asymmetry of the ferromagnetic order. Starting from an undoped atomically thin LaMnO
film, we electrostatically dope the material with electrons or holes according to the polarity of a voltage applied across an ionic liquid gate. Magnetotransport characterization reveals that an increase of either electron-doping or hole-doping induced ferromagnetic order in this antiferromagnetic compound, and leads to an insulator-to-metal transition with colossal magnetoresistance showing electron-hole asymmetry. These findings are supported by density functional theory calculations, showing that strengthening of the inter-plane ferromagnetic exchange interaction is the origin of the ambipolar ferromagnetism. The result raises the prospect of exploiting ambipolar magnetic functionality in strongly correlated electron systems.
The collapse strength is analyzed for periodic planar lattices under uniaxial compression. In part I, the quasi-static strengths of the lattices are predicted by limit analysis 1. In contrast to part ...I, the dynamic crushing is studied by finite element simulations in this part. Under different impact velocities, the deformation modes and the average stress of lattices with various relative densities are studied, whilst the emphasis is put on the inertia effect. It is found that the average stress increases with the impact velocity, the density of the base material and the relative density of the lattice. Therefore, the average dynamic stress can be expressed as the sum of the average static stress and the dynamic enhancement caused by the inertia effect. The average dynamic stress for membrane-dominated lattices is higher than that of bending-dominated lattices, but the difference in the dynamic enhancement is not as significant as that in the static collapse stress. According to the shock wave theory, the empirical formula of a hexagonal lattice under uniaxial compression is modified and generalized to all the interested lattices. The empirical formulas based on the shock wave theory agree well with the FE simulations, especially for the membrane-dominated lattice that has less transverse expansion.
This paper presents a design flexible, innovative strategy that can be used for the development, restoration and/or repairing of neutron shielding products in the near future. Cold spray additive ...manufacturing technique was employed to deposit a 6 mm thick neutron shielding B4C/Al composite coating on a 6061-T6 cylindrical substrate. Microstructure, mechanical behavior and neutron shielding performance of the free standing coating were investigated at different heat treatment conditions in the order: 200, 300, 400 and 500 °C. Microstructure evolutions were characterized using scanning electron microscopy (SEM), electron backscattered diffraction (EBSD), laser confocal scanning microscopy (LSM), X-ray diffraction (XRD) techniques, while mechanical properties were investigated via tensile and hardness tests. It was revealed that due to the presence of large amount of inter-splats' defects and intensive cold working, the as-deposited coating exhibited poor strength and fractured in a brittle manner. Moreover, as the heat treatment temperature was increased, the coating gradually recovered the ductility and gained strength due to progressive bonding/healing of inter-splat boundaries through recovery and recrystallization mechanisms. The coating heat-treated at 500 °C displayed maximum ductility (1.4%) and strength (60 MPa) with minimum porosity level of 1.9%. Neutron shielding results showed attenuation of thermal neutrons with increasing sample thickness. Neutron shielding results also displayed a slight improvement in the neutron shielding performance of the sample heat-treated at 500 °C.
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•A 6 mm thick B4C/Al neutron shielding coating was fabricated through CSAM.•Heat treatment can improve the mechanical properties of the as-sprayed coating.•Mechanical properties were rejuvenated by recovery/recrystallization mechanisms.•Neutron shielding results showed attenuation of thermal neutrons with thickness.
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