Aggregation Dynamics Characteristics of Seven Different Aß Oligomeric Isoforms-Dependence on the Interfacial Interaction.

The aggregation of ß-amyloid (Aß) peptides has been confirmed to be associated with the onset of Alzheimer's disease (AD). Among the three phases of Aß aggregation, the lag phase has been considered to be the best time for early Aß pathological deposition clinical intervention and prevention for potential patients with normal cognition. Aß peptide exists in various lengths in vivo, and Aß oligomer in the early lag phase is neurotoxic but polymorphous and metastable, depending on Aß length (isoform), molecular weight, and specific phase, and therefore hardly characterized experimentally. To cope with the problem, molecular dynamics simulation was used to investigate the aggregation process of five monomers for each of the seven common Aß isoforms during the lag phase. Results showed that Aß(1-40) and Aß(1-38) monomers aggregated faster than their truncated analogues Aß(4-40) and Aß(4-38), respectively. However, the aggregation rate of Aß(1-42) was slower than that of its truncated analogues Aß(4-42) rather than that of Aßpe(3-42). More importantly, Aß(1-38) is first predicted as more likely to form stable hexamer than the remaining five Aß isoforms, as Aß(1-42) does. It is hydrophobic interaction mainly (>50%) from the interfacial ß1 and ß2 regions of two reactants, pentamer and monomer, aggregated by Aß(1-38)/Aß(1-42) rather than by other Aß isoforms, that drives the hexamer stably as a result of the formation of the effective hydrophobic collapse. This paper provides new insights into the aggregation characteristics of Aß with different lengths and the conditions necessary for Aß to form oligomers with a high molecular weight in the early lag phase, revealing the dependence of Aß hexamer formation on the specific interfacial interaction.

Identification and characterization of the conformation and size of amyloid-ß (42) oligomers targeting the receptor LilrB2.

Experimental observations revealed that the amyloid-ß 42 oligomer (AßO) can directly bind to the LilrB2 D1D2(LDD) receptor with nanomolar-affinity, leading to changes in synaptic plasticity and cognitive deficits. However, the dependence of neurotoxicity on the morphology, size, and aggregation stage (SP1, SP2) of AßO, as well as the specific molecular mechanism of AßO-LDD interaction, remain uncertain. To address these uncertainties, we investigated the interaction between the LDD neuroreceptor and AßO with different Aß42 species (nontoxic species, toxic species, and protofibril) and sizes. Our results showed that the LDD selectively binds AßO species rather than the Aß42 monomer, accommodating various Aß42 dimers and trimers as well as SP2 AßO, in a specific pose in the pocket of the LDD receptor (region I). Additionally, protofibrils with exposed ß1/ß2 regions can also bind to region I of the LDD receptor, as observed experimentally (Cao, et al., Nat. Chem., 2018, 10, 1213; and Aim et al., Nat. Commun., 2021, 12, 3451). More extensively, we identified two additional regions of the LDD receptor, regions II and III, suitable for binding to larger AßO species at the SP1 with different molecular weights and conformations, accounting for the stronger binding strength obtained experimentally. We suggest that the two regions are more competitive than region I in causing toxicity by AßO binding. The detailed and systematic characterization for the complexes generated between the LDD receptor and various AßO species, including the protofibril, offers deep insight into the dependence of neurotoxicity on the AßO size and conformation at the molecular level, and provides novel and specific targets for drug design of Alzheimer's disease.

Origin of stronger binding of ionic pair (IP) inhibitor to Aß42 than the equimolar neutral counterparts: synergy mechanism of IP in disrupting Aß42 protofibril and inhibiting Aß42 aggregation under two pH conditions.

Fibrous aggregates of beta-amyloid (Aß) is a hallmark of Alzheimer's disease (AD). Several major strategies of drugs or inhibitors, including neutral molecules, positive or negative ions, and dual-inhibitor, are used to inhibit the misfolding or aggregation of Aß42, among which a kind of dual-inhibitor composed of a pair of positive and negative ions is emerging as the most powerful candidate. This knowledge lacks the origin of the strong inhibitory effect and synergy mechanisms blocking the development and application of such inhibitors. To this end, we employed 1 : 1 ionic pairs (IP) of oppositely charged benzothiazole molecules (+)BAM1-EG6 (Pos) and (-)BAM1-EG6 (Neg) as well as equimolar neutral BAM1-EG6 (Neu) counterpart at two pH conditions (5.5 and 7.0) to bind Aß42 targets, Aß42 monomer (AßM), soluble pentamer (AßP), and pentameric protofibril (AßF) models, respectively, corresponding to the products of three toxic Aß42 development pathways, lag, exponential and fibrillation phases. Simulated results illustrated the details of the inhibitory mechanisms of IP and Neu for the AßY (Y = M, P, or F) in the three different phases, characterizing the roles of Pos and Neg of IP as well as their charged, hydrophobic groups and linker playing in the synergistic interaction, and elucidated a previously unknown molecular mechanism governing the IP-Aß42 interaction. Most importantly, we first revealed the origin of the stronger binding of IP inhibitors to Aß42 than that of the equimolar neutral counterparts, observing a perplexing phenomenon that the physiological condition (pH = 7.0) than the acidic one (pH = 5.5) is more favorable to the enhancement of IP binding, and finally disclosed that solvation is responsible to the enhancement because at pH 7.0, AßP and AßF act as anionic membranes, where solvation plays a critical role in the chemoelectromechanics. The result not only provides a new dimension in dual-inhibitor/drug design and development but also a new perspective for uncovering charged protein disaggregation under IP-like inhibitors.

Two novel phosphorus/potassium-degradation bacteria: Bacillus aerophilus SD-1/Bacillus altitudinis SD-3 and their application in two-stage composting of corncob residue.

For effective utilization of corncob residue to realize green circular production, using composting to obtain a high-quality and low-cost biomass fertilizer has become a very important transformation avenue. In this paper, two novel phosphorus/potassium-degradation bacterial strains were isolated from tobacco straw and identified as Bacillus aerophilus SD-1/Bacillus altitudinis SD-3 (abbreviated as SD-1/SD-3). These identified two novel bacteria SD-1/SD-3 show that the soluble phosphorus content of SD-1/SD-3 reached 360.89 mg L-1/403.56 mg L-1 in the shake flask test, and the mass concentration of soluble potassium is 136.56 mg L-1/139.89 mg L-1. In addition, the Laccase (Lac), Lignin peroxidase (LiP), and Manganese peroxidase (MnP) activities of SD-1 and SD-3 are 54.45 U L-1/394.84 U L-1/222.79 U L-1 and 46.27 U L-1/395.26 U L-1/203.98 U L-1 respectively, with the carboxy-methyl cellulase (CMCase) of 72.07 U mL-1 and 52.69 U mL-1. Meanwhile, the effects of three different combinations of cultures, i.e., no inoculation (K1), inoculation of SD-1/SD-3 on day 21 (K2) and on day 0 (G) are investigated to understand the influence on the degradation degree of corncob residue compost. The results of K2 compost treatment showed that the effective P/K content increased nearly 3.1/2.4 times, the degradation of cellulose/lignin was 49.1/68.0%, and the germination rate was 110.23%, which were higher than other experiment groups K1/G. In conclusion, knowledge of this paper will be very useful for the industrial sector for the treatment of complex corncob residue.

Mechanistic insight into the tautomerization of histidine initiated by water-catalyzed N-H and C-H cleavages.

The N-H and C-H activation is of great significance in organic chemistry and chemical industry fields, especially, in the utilization of petroleum raw materials. High NδH (tautomer of natural histidine) content would increase Alzheimer's disease risk. To inhibit this and improve the activation of N-H and C-H bonds, the isomerization mechanism from NδH to NεH of histidine-containing dipeptide catalyzed by water cluster was explored. The results discovered that water cluster assists this reaction by reducing the activation energies from 68.20 to 9.60 kcal mol-1, and its size not only affects the reaction rate but also determines the reaction pathway in a degree. Moreover, water cluster, taken as a potential green catalyst, is more effective on the reactions involving N-H and C-H bond cleavages than reported common toxic organometallic compounds and has different catalytic mechanisms. This work also provides some theoretical guidance for the modulation of Alzheimer's disease induced by histidine isomerization.

Recognition of Aß oligomer by LilrB2 acceptor: a tetracoordinated zipper mechanism.

Leukocyte immunoglobulin-like receptor B2 (LilrB2) is one of discovered cell surface ß-amyloid (Aß) receptors and taken as a promising therapeutic target for the treatment of Alzheimer's disease (AD). Aß42 oligomer rather than monomer is toxic to neuronal cells and can directly bind to LilrB2, resulting in synaptic loss and cognitive impairment in the development of AD. Therefore, uncovering the mechanism of interaction between Aß42 oligomer and LilrB2 becomes the first step to obtain a clear drug target and specific binding sites. Herein, a tetracoordinated mechanism for the Aß oligomer-LilrB2 binding was first put forward by employing Aß42 dimer mimic-antiparallel copies of Aß42 core fragment 16KLVFFA21, to bind LilrB2 as models, in which four key residues (F5/F6/L12/F14) in the Aß42 mimic are bound strongly with LilrB2 residue(s) or accommodated by four hydrophobic cavities in LilrB2 to generate a stable complex. Bi-dentate binding, however, cannot keep the complex Aß42 mimic-LilrB2 stable. The inhibitor fluspirilene can disturb the binding of four key residues of Aß42 to LilrB2, justifying the tetracoordinated zipper mechanism on the other hand.

Molecular engineering and activity improvement of acetylcholinesterase inhibitors: Insights from 3D-QSAR, docking, and molecular dynamics simulation studies.

The carbamate molecule rivastigmine was found to possess promising anti-acetylcholinesterase activity, enabling to target and occupy choline binding sites, and as a result, widely used to improve the treatment of Alzheimer's disease (AD). Higher dose of rivastigmine indicates rapid onset but more adverse effects, such as the large fluctuations in plasma concentration level and frequent incidence of gastrointestinal side effect. To solve the dilemma, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR), docking and molecular dynamics (MD) simulation strategy to construct a dismountable nanoplatform of inhibitor engineering, verification and application for improving the inhibitory activity per unit concentration. With the aid of 3D-QSAR method, we constructed a model by using 25 molecules reported, and verified well the rationality of these QSAR models by non-cross validation coefficient (r2 = 0.902). Docking and MD results show that rivastigmine, as a control, does target exactly the binding sites of acetylcholinesterase, those already observed experimentally, in turn, confirming the reliability of the present 3D-QSAR results. The method suggests that groups with electron-donating chemical property can improve the inhibitory activity, and screens out two novel inhibitors L-1 and L-2 with more activity from database (about 8000 compounds). Moreover, L-1 and L-2 not only target exactly the same binding sites of acetylcholinesterase as the rivastigmine does, but also hold stronger binding energy, showing a more powerful inhibitory ability. More broadly, this work showcases an approach in the engineering of carbamate inhibitors to enhance their inhibitory activity using electron-donating groups, which simplifies the design process of complex bioactive molecules.

Toxicity Mechanism of Aß42 Oligomer in the Binding between the GABABR1a sushi1 Domain and Amyloid Precursor Protein 9mer: A Mechanism like Substitution Reaction.

Amyloid-ß peptide (Aß), characterized by its abnormal folding into neurotoxic aggregates, impairs synaptic plasticity and causes synaptic loss associated with Alzheimer's disease (AD). The neurotoxicity of Aß oligomers via the binding to various cell-surface receptors was frequently observed experimentally; however, the toxic mechanism still remains unknown. In this paper, we study the intervention of Aß oligomers to the receptor-peptide binding in the GABABR1a sushi1-APP 9mer complex, a key node in increasing short-term synaptic facilitation in the mouse hippocampus and decreasing neuronal activity by inhibiting neurotransmitter release by molecular dynamics simulations. The residue types of Aß42 oligomers involved in the intervention and core contact areas of the receptor were first identified, by which an unprecedented toxicity mechanism of Aß42 oligomers is proposed. These involved residues of Aß42 oligomers are positively charged residues Asp and Glu, and the core area of GABABR1a sushi1 domain is the Coil one, sharing the rich negatively charged residues R19/R21/R25/R45 with the pocket, in which APP 9mer is locked. The presence of an Aß42 oligomer rather than of a monomer stretches these key residues in the core area and consequently "unlocks and releases" the APP 9mer from its initial pocket, unsteadying the sushi1 domain and taking into toxic effect. It looks like a chemical "substitution" reaction, Aß42 oligomer + GABABR1a sushi1-APP 9mer complex → Aß42 oligomer-GABABR1a sushi1 complex + APP 9mer. Further analysis reveals that the toxicity of Aß42 oligomer to GABABR1a sushi1 domain stability depends on the residue number of the contact area and the size of Aß42 oligomer, in which semi-extended trimeric Aß42 oligomer is identified as the most toxic one. This work provides a novel insight into the mechanism of Aß oligomeric toxicity to neuroreceptors and sets an important precedent for dealing with Aß oligomeric toxicity to other receptors at the molecular level.

Identification of the probable structure of the sAPPα-GABABR1a complex and theoretical solutions for such cases.

Amyloid precursor protein (APP) is the core of the pathogenesis of Alzheimer's disease (AD). Existing studies have shown that the soluble secreted APP (sAPPα) fragment obtained from the hydrolysis of APP by α-secretase has a synaptic function. Thereinto, a nine-residue fragment (APP9mer) of the extension domain region of sAPPα can bind directly and selectively to the N-terminal sushi1 domain (SD1) of the γ-aminobutyric acid type B receptor subunit 1a (GABABR1a) protein, which can influence synaptic transmission and plasticity by changing the GABABR1a conformation. APP9mer is a highly flexible, disordered region, and as such it is difficult to experimentally determine the optimal APPmer-SD1 binding complex. In this study we constructed two types of APP9mer-SD1 complexes through molecular docking and molecular dynamics simulation, aiming to explore the recognition function and mechanism of the specific binding of APP9mer with SD1, from which the most probable APPmer-SD1 model conformation is predicted. All the data from the analyses of RMSD, RMSF, PCA, DCCM and MM/PBSA binding energy as well as comparison with the experimental dissociation constant Kd suggest that 2NC is the most likely conformation to restore the crystal structure of the experimental APP9mer-SD1 complex. Of note, the key recognition residues of APP9mer are D24, D25, D27, W29 and W30, which mainly act on the 9-45 residue domain of SD1 (consisting of two loops and three short ß-chains at the N-terminus of SD1). The mini-model with key residues identified establishes the molecular basis with deep insight into the interaction between APP and GABABR1a and provides a target for the development of therapeutic strategies for modulating GABABR1a-specific signaling in neurological and psychiatric disorders. More importantly, the study offers a theoretical solution for how to determine a biomolecular structure with a highly flexible, disordered fragment embedded within. The flexible fragment involved in a protein structure has to be deserted usually during the structural determination with experimental methods (e.g. X-ray crystallography, etc.).

Small-Molecule Targeted Aß42 Aggregate Degradation: Negatively Charged Small Molecules Are More Promising than the Neutral Ones.

Heavy evidence has confirmed that Aß42 oligomers are the most neurotoxic aggregates and play a critical role in the occurrence and development of Alzheimer's disease by causing functional neuron death, cognitive damage, and dementia. Disordered Aß42 oligomers are challenging therapeutic targets, and no drug is currently in clinical use that modifies the properties of their monomeric states. Here, a negatively charged molecule (ER), rather than the neutral TS1 one, is identified by a molecular dynamics simulation method to be more capable of binding and sequestering the intrinsically disordered amyloid-ß peptide Aß42 in its soluble pentameric state as well as its monomeric components. Results reveal that the ERs interact with Aß and inhibit the primary nucleation pathways in its aggregation process in entropic expansion mechanism for both Aß42 and Aß40 oligomers but with opposite characteristics of hydrophobic surface area (HSA). The interaction between Aß42 oligomer and either charged ER or neutral TS1/TS0 characterizes decreased HSA, and the decrease in ER-involved case is highly visible, consistent with the observations from in silico and in vitro studies. By contrast, the presence of these inhibitors causes the HSA of Aß40 oligomer to change undetectably and there is even a bit of increase in the histidine isomerized Aß40 oligomer. The HSA distinction between Aß42 and Aß40 oligomer is possibly derived from the different effects of M35-inhibitor interaction, which is analogous to the effect of M35 oxidation. In comparison with the neutral TS1/TS0 inhibitors, ER is more prone to bind the residues located in the central (ß1) and C-terminal (ß2) regions of Aß42 peptide, two key nucleation regions for Aß intramolecular folding, intermolecular aggregation, and assembly. Notably, ER can strongly bind the charged residues, such as K16, K28, D23, to greatly disturb the potential stabilizer (e.g., salt-bridge, etc.) in metastable Aß42 oligomers and protofibrils. These results illustrate the strategy of overcoming Alzheimer's disease from inhibiting its early stage Aß aggregation with two kinds of small molecules to alter their behavior for therapeutic purposes and strongly recommend paying more attention to the engineering and development of negatively charged inhibitors, the long-term underappreciated ones, targeting the early stage Aß aggregates.

A simple general descriptor for rational design of graphyne-based bifunctional electrocatalysts toward hydrogen evolution and oxygen reduction reactions.

The high cost and relative scarcity of platinum (Pt) restrict large-scale commercialization of fuel cells, which has spurred researchers to develop low-cost alternatives integrating with high hydrogen evolution reaction (HER) and oxygen reduction reaction (ORR) catalytic activity. Herein, we performed density functional theory (DFT) calculations to explore the electrocatalytic activity of graphyne nanotubes (GyNTs). Several GyNTs were found to be potential metal-free electrocatalysts, with both HER and ORR activity superior to Pt. Moreover, we revealed a linear relationship between the Gibbs free energy change of O2 adsorption (ΔGOOH) and binding energy of H adsorption (ΔEH), which could be attributed to the fact that both the CO bond of OOH adsorption and the CH bond of H adsorption are single bonds. Therefore, ΔEH is proposed as a general descriptor for the rational design of bifunctional graphyne materials toward HERs and ORRs. Our findings provide a simple strategy for the rational design of bifunctional materials.

Amine-functionalized ionic liquids for CO2 capture.

In petroleum industry, the release of more and more carbon dioxide (CO2) brings greenhouse effect and even results in climate change, leading CO2 capture to become an urgent issue. To design ideal and effective absorbent, interaction mechanism for CO2 capture was systematically investigated in a series of imidazolium-based ionic liquids (ILs). The potential effects of alkyl side chain, electron-philic halogen (F, Cl, Br) atom(s), electron-denoting groups OH and NH2 (bound on cation or/and anion), and water solvent were disclosed on CO2 capture using CAM-B3LYP functional with SMD-GIL solvation model, and the most potential green effective absorbent was predicted. This work provides an explicit idea and theoretical basis about the design of desired IL for CO2 capture. Graphical abstract In present work, no/halogen/amino/hydroxy-functionalized imidazolium tetrafluoroborate ILs were studied for CO2 absorption at the CAM-B3LYP/6-311++G** level of theory by SMD-GIL solvation model. NH2 is more potent group in absorbing CO2 than halogen and OH, and its number is proportional to the adsorption capacity of IL. A potentially high-capacity CO2 absorbent with four NH2 groups was predicted. In addition, the mixture of water could further enhance such chemical absorption by lowering the activation energy barriers and viscosity of IL.

γ-Graphyne nanotubes as defect-free catalysts of the oxygen reduction reaction: a DFT investigation.

Graphyne materials are potential candidates to fabricate low-cost but efficient metal-free oxygen reduction reaction (ORR) electrocatalysts. However, due to the coexistence of sp and sp2 carbon atoms in graphyne, some factors playing important roles in determining the ORR activity have received little attention. In the present paper, we carried out thorough density functional theory (DFT) calculations to study the curvature effect on the ORR activity of γ-graphyne. Our results suggest that the (5, 0)-γGyNT would be an excellent metal-free ORR catalyst. Its limiting potential was computed to be 0.80 V and the corresponding active sites occupy up to 16.7% in content, much better than previously reported CACs. Moreover, it is revealed that the curvature can tune the degree of exposure of p electrons of active sites, thus tuning the ORR activity. Our findings are beneficial for further understanding catalytic behavior on graphyne related materials and we suggest a new strategy to design high performance metal-free ORR catalysts.

Novel Disassembly Mechanisms of Sigmoid Aß42 Protofibrils by Introduced Neutral and Charged Drug Molecules.

Alzheimer's disease (AD) is characterized by fibrillar deposits of amyloid-ß (Aß) peptides and neurofibrillary tangles of Tau proteins. Aß peptides are composed of 37-49 residues, among which the Aß42 isoform is particularly toxic and aggregation-prone and is enriched in the plaques of AD brains and thus considered central to the development of AD. Therefore, disaggregation and disruption provide potential therapeutic approaches to reduce, inhibit, and even reverse Aß aggregation. Here we capture the atomic-level details of the interactions between sigmoid Aß42 fibril 2MXU or 5KK3 and either natural tanshinone compounds TS1 or TS0 or negatively charged ER, proposing two unprecedented disassembly mechanisms. Natural TS1 or TS0 prefers to insert into the cavity together with part at the surface of the 2MXU to open up the mouth and twist the conformation, destroying the ordered growth of subsequent monomers along the fibril axis. For the more compact two-fold 5KK3 , attachment of TS1 or TS0 at the surface including some inserted in cavity results in the separation of the two folds. In the two sigmoid fibril systems, it is no longer applicable for the routine criteria to assess Aß42 fibril disassembly by introduction of these drugs, such as either reduced H-bond number, decreased ß-sheet contents, or both. ER, like-charged to Aß42 fibril, is especially exceptional, and departs utterly from the neutral ones to disassemble Aß42 fibril. Besides the inapplicable routine criteria, positive binding energy between ER and Aß42 fibril also deviates from the hypotheses of "ligands exhibiting greater affinity for the ß-amyloid peptide are effective at altering its aggregation and inhibiting cell toxicity" ( Cairo et al. , Biochemistry 2002 , 41 , 8620 - 8629 ) but results in stronger disassembly effect on the two kinds of sigmoid Aß42 fibrils than neutral TS0 or TS1. The disassembly power of charged ER molecules derives from its stronger deformation ability to the conformation of Aß42 fibril than the neutral ones, twisting the one-fold 2MXU into tapered-shape and separating two-fold 5KK3 in two parts further, which is in great agreement with experimental observations ( Irwin et al. Biomacromolecules 2013 , 14 ( 1 ), 264 - 274 ). The unusual disassembly mechanisms fill the gaps and offer an alternative direction in engineering new inhibitors to treat AD.

Synergy of sp-N and sp2-N codoping endows graphdiyne with comparable oxygen reduction reaction performance to Pt.

Nitrogen doped graphdiyne (NGDY) has been reported to have comparable oxygen reduction reaction (ORR) performance to Pt-based catalysts. However, the source of this enhanced ORR performance is not clearly understood. Herein, density functional theory calculations were performed to study the detailed ORR process on NGDY. The theoretically predicted overpotential (η) of GDY materials was 0.442 V, which is comparable to that of Pt-based catalysts, suggesting that GDY is a candidate for non-expensive metal-free ORR catalyst. Our results revealed that the good ORR performance of NGDY originates from the synergy of sp-N and sp2-N, which rules out the experimental proposal that sp-N doping is the dominating factor. Our results further suggest that local positive charge is not a definite descriptor to predict the ORR performance of GDY; instead ΔGO shows a better correlation with performance. Furthermore, it was revealed that the adsorption site is crucial for determining ORR performance, which should not be ignored to fully understand the catalytic activity of GDY-based materials.

An Original Monomer Sampling from a Ready-Made Aß42 NMR Fibril Suggests a Turn-ß-Strand Synergetic Seeding Mechanism.

Aggregation of amyloid beta (Aß) is a central step of Alzheimer's disease. Aß42 monomers are building blocks in the formation of both "on pathway" intermediate structures and "off pathway" oligomers. How to sample an Aß monomer becomes a problem however due to the instinct of Aß high flexibility and diversity as well as aggregation propensity. Currently, (1) most samplings focus on either the ready-made helix-rich 1Z0Q/1IYT NMR structure, or the completely extended conformation, but (2) few on a ready-made Aß NMR fibril (i. e., 2BEG). Here we compare the simulation results from sampling in scheme (1) with that in scheme (2), and find that the coil and ß-sheet contents in the 1Z0Q-sampled system are comparable to the counterparts in the 2BEG-sampled system, but with a large difference in simulation time and dynamics character. 1Z0Q-sampled system not only takes several times longer than the 2BEG-sampled one, and only ß1-seeding dynamics characteristic is observed probably due to far insufficient conformation transition in the limited simulation time. Two dynamics characteristics of Aß42 folding observed experimentally, that either ß1 region or ß2 region aggregates first, reproduce in the present simulations for 2BEG-sampled system however, suggesting a preferential sampling in the future simulation. In addition, a turn-ß-strand synergetic seeding mechanism of aggregation is first proposed based on the trajectory analyses on the four regions of Aß42 chain.

Tautomerization Effect of Histidines on Oligomer Aggregation of ß-Amyloid(1-40/42) during the Early Stage: Tautomerism Hypothesis for Misfolding Protein Aggregation.

As the intrinsic origin of the hypothesis for ß-amyloid (Aß) from Alzheimer's disease, histidine behaviors were found to play a crucial role in Aß aggregation. To investigate the histidine behaviors during the early stage of aggregation, Aß40/42 pentamers with different histidine isomer states were simulated at the atomic level. Results show that five Aß40 (δδδ) and Aß42 (εδδ) monomers can rapidly decrease the aggregation threshold, promote stable pentamer formation, and increase pentamer contents by 51.8% and 56.7%, respectively, as compared with the values of their wild-type (εεε) counterparts. Additionally, pentamers of Aß40 (δδδ) and Aß42 (εδδ) have different aggregation pathways and disassembly species, Tr+D and Te+M, during the growth of the pentamer. This work discloses the significance of histidine tautomerization in Aß aggregation, implying a potential way to control Aß aggregation and develop the assembly inhibitors.

Effects of double-atom vacancies on the electronic properties of graphyne: a DFT investigation.

Vacancy defects are one of the key impurities that strongly affect the properties of materials. In the present study, some different double-atom vacancies were introduced into α-graphyne (Gy), ßGy, and γGy, depending on their own structural characteristics. Subsequently, density functional theory (DFT) calculations were carried out to evaluate the changes in the structural and electronic properties induced by the double-atom vacancies. The results indicated that the double-atom vacancies only lead to an in-plane structural rearrangement of all three of the Gy systems. It was further revealed that the position of the double-atom vacancies is a crucial factor in the manipulation of the electronic properties of αGy and ßGy as compared with γGy. Our work is expected to yield new Gy materials with the desired properties obtained by altering the position of induced double-atom vacancies.

Positive effect of strong acidity on the twist of Aß42 fibrils and the counteraction of Aß42 N-terminus.

pH is a crucial factor in terms of affecting the aggregation and morphology of ß-Amyloid and hence a focus of study. In this study, structural and mechanical properties of a series of models (5, 6, …, 30 layer) of one-fold Aß42 fibrils at pH 1.5, 3.0 and 7.5, have been computed by using all-atom molecular dynamics simulations. 12, 14, and 15 layers are established to be the smallest realistic models for Aß42 fibrils at pH 1.5, 3.0 and 7.5, with twist angles of 0.40°, 0.34°, 0.31° respectively, disclosing the favorable effect of strong acidity on fibril twist. However, these angles are all lower than that (0.48°) determined for the truncated Aß17-42 fibril at pH 7.5, indicating that the disordered N-terminal depresses greatly the fibril twist and the lower pH disfavors the depression. Three commonly used indices to measure the fibril properties, namely number of H-bonds, interstrand distance and ß-sheet content have imperceptible changes with the pH alternation, therefore changes in fibril twist can be taken as a probe to monitor fibril properties. By contrast, N-terminus is determined not only to inhibit the U-shaped fibril twist by hampering the stagger between ß1 and ß2 strands, but also to play a vital carrier role in feeling solution (i.e., pH, salt) changes. These results can help design the nextgeneration of amyloid materials for state-of-the-art bio-nano-med applications by changing the solution pH or modifying chain length.

Effect of pH on Aß42 Monomer and Fibril-like Oligomers-Decoding in Silico of the Roles of pK Values of Charged Residues.

Amyloid beta-peptide (Aß) is the key to developing Alzheimer's disease. Experiments have confirmed that different acidity influences directly not only the structural morphology and population of Aß oligomers, but also the toxicity. The atomic-level association between the pH, charged residues, and Aß properties remains obscure. Herein, conformational changes of Aß42 monomer, fibril-like trimer, and pentamer in the medium pH range of 4.0-7.5 are studied. The results reveal that, as the pH changes from 7.5 to the isoelectric pH, His6, His13, and His14 are protonated in turn, successively approach the center of mass of folded Aß monomer, trigger ionic interactions and changes of neighboring turns (Asp7-Ser8, His14-Lys16) and even a distant one (Leu34-Met35), as well as concomitant changes of secondary structure, and promote the conformation transition from unfolded to folded. This observation discloses that protonation can convert these charged residues from originally hydrophilic to "hydrophobic-like". For fibril-like oligomers, the pH susceptibility essentially stems from the pK values of charged residues in the context of the Aß fibril, and in turn one can predict the dynamic behavior of these residues in the processes of dissociation or stabilization of a fibril by comparing the pK values of residues involved in salt bridges in the normal state with those in the current context. This idea is justified by two fibril models and appears to be applicable to other peptides and their fibril systems.