Commonly used methods for determining protein structure, including X-ray crystallography and single-particle reconstruction, often provide a single and unique three-dimensional (3D) structure. However, in these methods, the protein dynamics and flexibility/fluctuation remain mostly unknown. Here, we utilized advances in electron tomography (ET) to study the antibody flexibility and fluctuation through structural determination of individual antibody particles rather than averaging multiple antibody particles together. Through individual-particle electron tomography (IPET) 3D reconstruction from negatively-stained ET images, we obtained 120 ab-initio 3D density maps at an intermediate resolution (~1–3 nm) from 120 individual IgG1 antibody particles. Using these maps as a constraint, we derived 120 conformations of the antibody via structural flexible docking of the crystal structure to these maps by targeted molecular dynamics simulations. Statistical analysis of the various conformations disclosed the antibody 3D conformational flexibility through the distribution of its domain distances and orientations. This blueprint approach, if extended to other flexible proteins, may serve as a useful methodology towards understanding protein dynamics and functions.
Pentazole anion, the best candidate of full-nitrogen energetic materials, can be isolated only from acidic solution with a puzzled reason that is critical to raising the production yield and energy density of the substance. Herein, we report for the first time the discovery of the dual aromaticity (π and ) of cyclo-N5ˉ, which makes the anion unstable in nature but confers additional stability in acidic surroundings. In addition to the usual πaromaticity, similar to that of the prototypical benzene, five lone pairs are delocalized in the equatorial plane of cyclo-N5ˉ, forming additional -aromaticity. It is the compatible coexistence of the inter-lone-pair repulsion and inter-lone-pair attraction within the aromatic system that makes the naked cyclo-N5ˉ highly reactive to electrophiles and easily broken. Only in sufficiently acid solution can the cyclo-N5ˉ become unsusceptible to the electrophilic attack and gain extra stability through the formation of hydrogen-bonded complex from surrounding electrophiles; otherwise the cyclo-N5ˉ cannot be productively isolated. The dual aromaticity discovered in cyclo-N5ˉ is expected to be a universal nature of the pnictogen five-membered ring systems.
Extensive density functional theory (DFT) calculation and data analysis on molecular and crystal level features of 60 reported energetic materials (EMs) allowed us to define key descriptors that are characteristics of these compounds' thermostability. We see these descriptors as reminiscent of "Lipinski's rule of 5", which revolutionized the design of new orally active pharmaceutical molecules. The proposed descriptors for thermostable EMs are of a type of molecular design, location and type of the weakest bond in the energetic molecule, as well as specific ranges of oxygen balance, crystal packing coefficient, Hirshfeld surface hydrogen bonding, and crystal lattice energy. On this basis, we designed three new thermostable EMs containing bridged, 3,5-dinitropyrazole moieties, HL3, HL7, and HL9, which were synthesized, characterized, and evaluated in small-scale field detonation experiments. The best overall performing compound HL7 exhibited an onset decomposition temperature of 341 °C and has a density of 1.865 g cm −3 , and the calculated velocity of detonation and maximum detonation pressure were 8517 m s −1 and 30.6 GPa, respectively. Considering HL7's impressive safety parameters [impact sensitivity (IS) = 22 J; friction sensitivity (FS) = 352; and electrostatic discharge sensitivity (ESD) = 1.05 J] and the results of small-scale field detonation experiments, the proposed guidelines should further promote the rational design of novel thermostable EMs, suitable for deep well drilling, space exploration, and other high-value defense and civil applications.
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