Insights into the aggregation mechanism of RNA recognition motif domains in TDP-43: a theoretical exploration.

The transactive response DNA-binding protein 43 (TDP-43) is associated with several diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) due to pathogenic aggregations. In this work, we examined the dimer, tetramer and hexamer models built from the RRM domains of TDP-43 using molecular dynamics simulations in combination with the protein-protein docking. Our results showed that the formations of the dimer models are mainly achieved by the interactions of the RRM1 domains. The parallel ß-sheet layers between the RRM1 domains provide most of the binding sites in these oligomer models, and thus play an important role in the aggregation process. The approaching of the parallel ß-sheet layers from small oligomer models gradually expand to large ones through the allosteric communication between the α1/α2 helices of the RRM1 domains, which maintains the binding affinities and interactions in the larger oligomer models. Using the repeatable-superimposing method based on the tetramer models, we proposed a new aggregation mechanism of RRM domains in TDP-43, which could well characterize the formation of the large aggregation models with the repeated, helical and rope-like structures. These new insights help to understand the amyloid-like aggregation phenomena of TDP-43 protein in ALS and FTLD diseases.

Theoretical Studies on the Binding Mode and Reaction Mechanism of TLP Hydrolase kpHIUH.

In this work, we have investigated the binding conformations of the substrate in the active site of 5-HIU hydrolase kpHIUH and its catalytic hydrolysis mechanism. Docking calculations revealed that the substrate adopts a conformation in the active site with its molecular plane laying parallel to the binding interface of the protein dimer of kpHIUH, in which His7 and His92 are located adjacent to the hydrolysis site C6 and have hydrogen bond interactions with the lytic water. Based on this binding conformation, density functional theory calculations indicated that the optimal catalytic mechanism consists of two stages: (1) the lytic water molecule is deprotonated by His92 and carries out nucleophilic attack on C6=O of 5-HIU, resulting in an oxyanion intermediate; (2) by accepting a proton transferred from His92, C6-N5 bond is cleaved to completes the catalytic cycle. The roles of His7, His92, Ser108 and Arg49 in the catalytic reaction were revealed and discussed in detail.

Dramatically Enhanced and Red-shifted Photoluminescence Achieved by Introducing an Electron-withdrawing Group into a Non-traditional Luminescent Small Organic Compound.

Small organic compounds without any traditional fluorescent chromophores are generally non-emissive, and only very few are reported to emit weak blue fluorescence. Here we synthesized a non-traditional luminescent small organic compound N-(2,2,2-trifluoroethyl)acrylamide (TFAM) with dramatically enhanced and red-shifted photoluminescence by introducing a strong electron-withdrawing group into acrylamide (AM). Very impressively, TFAM emits cyan (472 nm) and yellow-green (560 nm) fluorescence in solutions and solid state, respectively. TFAM also shows aggregation-induced emission enhancement (AIEE) and excitation-dependent fluorescence (EDF) characteristics, as well as temperature and metal cations-responsive fluorescence. Theoretical calculations show that the introduction of electron-withdrawing group leads to a lower energy gap between the HOMO-LUMO energy levels in TFAM than in AM. And strong cooperative hydrogen bonds are formed in TFAM molecules, resulting in rigidification of molecular conformations. The study provides a strategy for preparing non-traditional luminescent compounds with enhanced and red-shifted photoluminescence.

N-Nitrosation Mechanism Catalyzed by Non-heme Iron-Containing Enzyme SznF Involving Intramolecular Oxidative Rearrangement.

The non-heme iron-dependent enzyme SznF catalyzes a critical N-nitrosation step during the N-nitrosourea pharmacophore biosynthesis in streptozotocin. The intramolecular oxidative rearrangement process is known to proceed at the FeII-containing active site in the cupin domain of SznF, but its mechanism has not been elucidated to date. In this study, based on the density functional theory calculations, a unique mechanism was proposed for the N-nitrosation reaction catalyzed by SznF in which a four-electron oxidation process is accomplished through a series of complicated electron transferring between the iron center and substrate to bypass the high-valent FeIV═O species. In the catalytic reaction pathway, the O2 binds to the iron center and attacks on the substrate to form the peroxo bridge intermediate by obtaining two electrons from the substrate exclusively. Then, instead of cleaving the peroxo bridge, the Cε-Nω bond of the substrate is homolytically cleaved first to form a carbocation intermediate, which polarizes the peroxo bridge and promotes its heterolysis. After O-O bond cleavage, the following reaction steps proceed effortlessly so that the N-nitrosation is accomplished without NO exchange among reaction species.

The Role of the Hydrogen Bond between Piperazine and Fullerene Molecules in Stabilizing Polymer:Fullerene Solar Cell Performance.

Piperazine has been recently reported as a stabilizer for polymer:fullerene solar cells that can minimize the "burn-in" degradation of the cell. In this paper, the influence of N-substituents on the stabilization effect of piperazine in P3HT:PC61BM cells was investigated. Results confirmed that only piperazine derivatives (PZs) with N-H bonds showed the stabilization effect, whereas the bis-alkyl-substituted piperazine compounds cannot improve the stability. An efficient photon-induced electron transfer (PET) process between PZ and PC61BM was only detected for the N-H-containing PZ:PC61BM blends, corresponding very well to the stabilization effect of the PZs, which indicates that the PET process between PZ and PC61BM stabilizes the cell performance, and the N-H bond plays a critical role ensuring the PET process and the consequent stabilization effect. Both 1H-NMR spectroscopy and theoretical calculations confirmed the formation of N-H···O-C and N-H···π bonds for the PC61BM:piperazine adduct, which was considered as the driving force that promotes the PET process between these two components. In addition, comparison of the calculated electron affinity energy (EA) and excitation energy (EEx) of PC61BM with/without piperazine confirmed that piperazine doping is able to promote the electron transfer (which leads to the formation of PC61BM anions) than the energy transfer (leads to the formation of PC61BM excitons) between P3HT and PC61BM, which is beneficial for the performance and stability improvement.