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The abnormal self-assembly of amyloid-β (Aβ) peptides into toxic fibrillar aggregates is associated with the pathogenesis of Alzheimer's disease (AD). The inhibition of β-sheet-rich oligomer formation is considered as the primary therapeutic strategy for AD. Previous experimental studies reported that norepinephrine (NE), one of the neurotransmitters, is able to inhibit Aβ aggregation and disaggregate the preformed fibrils. Moreover, exercise can markedly increase the level of NE. However, the underlying inhibitory and disruptive mechanisms remain elusive. In this work, we performed extensive replica-exchange molecular dynamic (REMD) simulations to investigate the conformational ensemble of Aβ1-42 dimer with and without NE molecules. Our results show that without NE molecules, Aβ1-42 dimer transiently adopts a β-hairpin-containing structure, and the β-strand regions of this β-hairpin (residues 15QKLVFFA21 and 33GLMVGGVV40) strongly resemble those of the Aβ fibril structure (residues 15QKLVFFA21 and 30AIIGLMVG37) reported in an electron paramagnetic resonance spectroscopy study. NE molecules greatly reduce the interpeptide β-sheet content and suppress the formation of the above-mentioned β-hairpin, leading to a more disordered coil-rich Aβ dimer. Five dominant binding sites are identified, and the central hydrophobic core 16KLVFFA21 site and C-terminal 31IIGLMV36 hydrophobic site are the two most favorable ones. Our data reveal that hydrophobic, aromatic stacking, hydrogen-bonding and cation-π interactions synergistically contribute to the binding of NE molecules to Aβ peptides. MD simulations of Aβ1-42 protofibril show that NE molecules destabilize Aβ protofibril by forming H-bonds with residues D1, A2, D23, and A42. This work reveals the molecular mechanism by which NE molecules inhibit Aβ1-42 aggregation and disaggregate Aβ protofibrils, providing valuable information for developing new drug candidates and exercise therapy against AD.

This paper focuses on the thrust ripple of a permanent magnet linear synchronous motor (PMLSM). The PMLSMs with the North–South (NS) and consequent (C) poles are compared first. Then two magnetic regulating structures whose widths are τ and τ/3 (τ is the pole pitch) are proposed and set on the primaries, forming Modulars I and II structures, respectively. The effects that the modular structures exerting on the detent force and voltage harmonics are expounded. At last the modular primaries are selectively applied to the PMLSMs with different poles: the modular I whose magnetic regulating structure employs magnetic permeable material is applied to the C-pole PMLSM, and thus the thrust ripple caused by the voltage harmonics is suppressed remarkably. Whereas the magnetic regulating structure of the modular II which is nonmagnetic is used for the NS-pole PMLSM, helping to reduce the detent force and improve the average thrust.

Alzheimer's disease (AD) is associated with the aberrant self-assembly of amyloid-β (Aβ) protein into fibrillar deposits. The disaggregation of Aβ fibril is believed as one of the major therapeutic strategies for treating AD. Previous experimental studies reported that serotonin (Ser), one of the indoleamine neurotransmitters, and its derivative melatonin (Mel) are able to disassemble preformed Aβ fibrils. However, the fibril-disruption mechanisms are unclear. As the first step to understand the underlying mechanism, we investigated the interactions of Ser and Mel molecules with the LS-shaped Aβ

In this paper, an expansion planning method of transmission system considering flexibility is proposed. First of all, this paper puts forward evaluation indexes for evaluating the flexibility level of power system. A specific calculation method is proposed. Next, this paper further interprets the connotation of flexibility indexes and margins, and proposes modeling methods of uncertain elements and controllable elements considering flexibility. Then, this paper proposes a bi-level programming model combining network solutions and non-network solutions. The algorithm for solving the model is described. Finally, in the analysis of examples, through comparison with the traditional robust optimization methods, the advantage of deferring investment is reflected.

Complexity of power network increased is for that the scale and interconnectedness of power network are constantly expanding. It is particularly important to analyze network robustness and provide improvement strategies. The node gravity index was defined, and four intentional attack modes were designed to evaluate the robustness of complex networks. Based on the study of fractal mechanism, a strategy for reconstructing topology of complex networks based on maximum edge betweenness weight spanning tree was proposed, and its effectiveness and economy in improving robustness were verified by several examples.

The polishing resistance performance and abrasion resistance performance of aggregate affect the long-term skid resistance and durability of the pavement, but there is still a lack of a comprehensi...

The amyloid deposits of human islet amyloid polypeptide (hIAPP) are found in type 2 diabetes patients. hIAPP monomer is intrinsically disordered in solution, whereas it can form amyloid fibrils both in vivo and in vitro. Extensive evidence suggests that hIAPP causes the disruption of cellular membrane, and further induces cytotoxicity and the death of islet β-cells in pancreas. The presence of membrane also accelerates the hIAPP fibril formation. hIAPP oligomers and protofibrils in the early stage of aggregation were reported to be the most cytotoxic, disrupting the membrane integrity and giving rise to the pathological process. The detailed molecular mechanisms of hIAPP-membrane interactions and membrane disruption are complex and remain mostly unknown. Here in this review, we focus on recent computational studies that investigated the interactions of full length and fragmentary hIAPP monomers, oligomers and protofibrils with anionic, zwitterionic and mixed anionic-zwitterionic lipid bilayers. We mainly discuss the binding orientation of monomers at membrane surface, the conformational ensemble and the oligomerization of hIAPP inside membranes, the effect of lipid composition on hIAPP oligomers/protofibrils-membrane interactions, and the hIAPP-induced membrane perturbation. This review provides mechanistic insights into the interactions between hIAPP and lipid bilayers with different lipid composition at an atomistic level, which is helpful to understand the hIAPP cytotoxicity mediated by membrane. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

The formation of amyloid fibrils by α-synuclein (αS) protein inside the Lewy bodies and Lewy neurites is the prominent pathological hallmark of Parkinson's disease (PD). The fibrillation of αS in vitro is described by a nucleation-elongation process involving the formation of a critical nucleus. Finding the critical/smallest nuclei and effective inhibitors of αS aggregation is a crucial step for the development of drugs against PD. Recent experiments reported that dopamine (DA) and norepinephrine (NE), two prominent naturally occurring neurotransmitters, can effectively disrupt the preformed αS fibrils. The level of DA/NE in blood can be markedly increased by exercise. However, the size and structure of the critical nucleus and the disruptive mechanism by DA/NE are largely unknown. In this work, we performed multiple molecular dynamics (MD) simulations to find the critical nucleus size and examine the influences of DA/NE molecules on preformed αS44-96 (Greek-key-like core of full length αS) protofibrils. Our results show that the trimer is the critical nucleus for the αS44-96 fibril formation, and the tetramer is the minimal stable nucleus. When DA/NE molecules bind to the fibril-like trimer and tetramer, they strongly destabilize the αS protofibrils by disrupting the β-sheet structure and inter-chain E46-K80 salt bridges. Two common binding sites are identified for both DA and NE molecules on αS oligomers: residues 57-70 and 81-83. A different binding site is also observed, which is located at the N-terminal region (residues 45-52). The binding of DA/NE molecules to αS oligomers is mostly driven by hydrophobic and electrostatic interactions. We found two disruptive modes, and binding to the turn region of αS oligomers but disrupting the adjacent β-sheet structure is the dominant one. Our work identified the critical nucleus of Greek-key-like core of αS protofibrils and revealed the disruptive mechanism of αS protofibrils by DA/NE molecules, which may be helpful to the design of effective drugs against αS aggregation.

In this study, a simulation on the Micro-Deval test was presented for the aggregate wear properties measurement. The performance parameters including wear resistance, density, elasticity and Poisson ratio of the five kind aggregates were obtained by tests on red sandstone, basalt, limestone, quartzite and gneiss. The modified Micro-Deval test was adopted to analyze the wear resistance of five different aggregates according to the American Society for Testing and Materials (ASTM) standards. It was found that the Micro-Deval abrasion value increased exponentially rather than linear growth with the increase of the rotation times. The CoreLok multi-function aggregate density test equipment was adopted to measure the aggregate apparent density. The modulus of elasticity and Poisson ratio were measured by uniaxial compression test. All the test results provided accurate data support for aggregate virtual wear simulation. The aggregate 3D model, roller, balls, water and air models were built in ABAQUS software. Mohr Coulomb plasticity failure criterion was adopted in the simulation of Micro-Deval abrasion test. The calculation method of virtual abrasion value was proposed, and the simulation results of abrasion value were in line with the test result. It provided a new approach for the evaluation of aggregate anti-wear performance which had higher repeatability and controllability than the actual test.

The macro-texture of asphalt pavement greatly affects the traffic safety of driving. In this study, the 3D laser scanning data, which is captured from the pavements, is used for reverse modeling. FE software ANSYS is used to analyze the contact stress distribution of pavement macro-texture and tire. The results show that the macro texture will be affected by fatigue failure considering the size effect of coarse aggregate. The fatigue life distribution of pavements is analyzed using the fatigue analysis software FE-SAFE which is based on linear cumulative damage theory. The developing tendency of texture depth with respect to the number of loading times is obtained by analyzing the results of fatigue life. Compared with the results of accelerated loading test shows that the factor of fatigue failure has remarkably affected the macro texture under low loading times. This effect is gradually decreased with the increasing of cyclic loading times. Keywords: Fatigue failure, Reverse modeling, FE simulation, Pavement macro-texture, Fatigue life analysis

Hypoxia-inducible factor 1 (HIF-1) plays an essential role in the regulation of hypoxia in humans. This regulation is mediated by the interaction of the von Hippel-Lindau tumor suppressor protein (pVHL) with the hydroxylated HIF-1α at proline564 (Pro564). Experimental studies reported that Pro567 could also be hydroxylated. However, the conformational dynamics of the complex of pVHL with hydroxylated HIF-1α at Pro564 is not well understood, and whether hydroxylated Pro567 plays the similar essential role as Pro564 in regulating HIF-1α-pVHL interaction remains elusive. Herein, we performed all-atom molecular dynamics (MD) simulations on the pVHL/HIF-1α complexes with single hydroxylation at Pro564 and Pro567, double hydroxylation at both Pro564 and Pro567, and without hydroxylation. Our multiple MD simulations and binding energy calculations show that hydroxylation at Pro567 is less favorable for the binding of HIF-1α to pVHL, whereas hydroxylation at Pro564 results in an increase of structural rigidity of the pVHL/HIF-1α complex and an enhancement of the interactions between HIF-1α and pVHL. The different roles revealed here for Pro564 and Pro567 in regulating HIF-1α-pVHL interactions, together with the previous finding that HIF-prolyl hydroxylase PHD-3 participates in a negative feedback loop controlling the HIF-1 level, suggest that hydroxylated HIF-1α at Pro567 may perturb or may not participate in this negative feedback loop. Intriguingly, our simulation data and community network analysis demonstrate that the binding of hydroxylated HIF-1α at Pro564 to the β-domain of pVHL allosterically induces the conformational change of the α-domain via an optimal communication pathway from Pro564 of HIF-1α to S168 of the pVHL α-domain. This study reveals the different roles of Pro564 and Pro567 hydroxylation in HIF-1α in HIF-1α-pVHL interactions, which will be beneficial for developing effective strategies to treat hypoxia-related diseases and understanding the molecular basis of hypoxic training/exercise.

The accumulation of the human islet amyloid polypeptide (hIAPP) deposits in the pancreas is regarded as an important factor that leads to the depletion of islet β-cells and islet transplantation failure. In recent experiments, it was reported that a small organic molecule O4 inhibits the formation of hIAPP1-37 oligomers and fibrils. However, the interaction between O4 molecules and hIAPP oligomers is largely unknown on the atomic level. In this work, we studied the influence of O4 molecules on fibril-like hIAPP pentamer and decamer by performing atomistic molecular dynamics simulations. Our results show that O4 molecules mostly bind to the amyloid core region spanning residues 22NFGAI26 for both hIAPP pentamer and decamer, which leads to the local disruption of interpeptide β-sheets. The calculation of contact probability and binding energy indicates that the binding of O4 molecules is mostly driven by aromatic stacking and hydrophobic interactions. Our work reveals the detailed disruption mechanism of full-length hIAPP protofibrils by O4 molecules and may be helpful to the design of more efficient inhibitors against hIAPP aggregation.

The friction between tire and road surface is fundamentally depending on the molecular forces. In this paper, the nanoscale 3D contact model is employed to investigate the tire-aggregate friction mechanism. The tire and aggregate micro-structure are both constructed to evaluate the microscopic performance of tire-aggregate friction influence. Simulation results show for a high velocity, the energy dissipation of sliding on crystal structure is small, which results in a small friction coefficient; temperature will have influences on the friction coefficient, and with the increasing of velocity, the effect will gradually reduce. Keywords: Tire, Aggregate, Friction coefficient, Microscopic mechanism, MD simulation

The skid resistance performance of pavement is closely related to the micro-texture of pavement aggregate, while there is very few research on the relationship between micro-texture and the skid resistance. In this paper, the optical microscope is used to acquire the surface morphology of three types of aggregates including basalt, limestone and red sandstone respectively, where a total of 12 indicators are developed based on the surface texture information. The polishing effect on aggregate is simulated by Wehner/Schulze (W/S) device, during the polishing procedure, the skid resistance are measured by British Pendulum Tester (BPT). Based on the results of independent T-test and the polishing resistance analysis, it shows that the surface texture of basalt is significantly different between limestone and red sandstone. Three indicators including the average roughness (Ra), the kurtosis of the surface (Sku) and the mean summit curvature (Ssc) are selected to describe the characteristics of aggregate micro-texture based on the correlation analysis. The contribution of micro-texture to the skid resistance can be described with the secondary polynomial regression model by these indicators.

The skid resistance of asphalt pavement is affected by the surface macrotexture depth, especially when there is water on the pavement. Pavements with appropriate macrotexture can effectively ensure the traffic safety. However, previous research on characterisation methods still cannot properly reflect the three-dimensional (3D) information of pavement macrotexture, such as 3D features or distribution density of texture. In this study, a 3D laser scanner is used to collect the data of asphalt pavement texture, which will be used to reconstruct the 3D pavement model in the next step. Thereafter, the model is evenly meshed by a large number of micro elements. Based on the volume of elements, a method is proposed to characterise the 3D features of pavement macrotexture; the 3D characteristics of macrotexture can also be analysed quantitatively. Compared with four types of gradation of asphalt pavement, the results show that the proposed method can accurately represent the 3D macrostructure of asphalt pavement...

This paper presents an equivalent winding model of a small and medium permanent-magnet synchronous motor. The model considers fill factor and void ratio. To verify the model, two winding samples are made. One is annular and adopts ordinary enameled wires. The other is circle but adopts self-adhesion wires. Temperature rises of the winding samples supplied with different current densities are tested. The calculated and tested results were compared. The equivalent winding model is also used for the temperature calculation of a 6-pole/9-slot permanent magnet synchronous motor. The influence of fill factor and void ratio on the temperature rise of the motor is investigated, as well as two overload short time states are compared. Comparing with ignoring the effect of the void ratio, the winding temperature estimation error reduces about 5 °C. Finally, winding temperature rises of a prototype are tested. The results can provide some references for choosing a reasonable current density and improving the accuracy of motor temperature estimation.

The pathogenesis of Parkinson&rsquo, s disease (PD) is closely associated with the aggregation of &alpha, synuclein (&alpha, S) protein. Finding the effective inhibitors of &alpha, S aggregation has been considered as the primary therapeutic strategy for PD. Recent studies reported that two neurotransmitters, dopamine (DA) and norepinephrine (NE), can effectively inhibit &alpha, S aggregation and disrupt the preformed &alpha, S fibrils. However, the atomistic details of &alpha, S-DA/NE interaction remain unclear. Here, using molecular dynamics simulations, we investigated the binding behavior of DA/NE molecules and their structural influence on &alpha, S44&ndash, 96 (Greek-key-like core of full length &alpha, S) protofibrillar tetramer. Our results showed that DA/NE molecules destabilize &alpha, S protofibrillar tetramer by disrupting the &beta, sheet structure and destroying the intra- and inter-peptide E46&ndash, K80 salt bridges, and they can also destroy the inter-chain backbone hydrogen bonds. Three binding sites were identified for both DA and NE molecules interacting with &alpha, S tetramer: T54&ndash, T72, Q79&ndash, A85, and F94&ndash, K96, and NE molecules had a stronger binding capacity to these sites than DA. The binding of DA/NE molecules to &alpha, S tetramer is dominantly driven by electrostatic and hydrogen bonding interactions. Through aromatic &pi, stacking, DA and NE molecules can bind to &alpha, S protofibril interactively. Our work reveals the detailed disruptive mechanism of protofibrillar &alpha, S oligomer by DA/NE molecules, which is helpful for the development of drug candidates against PD. Given that exercise as a stressor can stimulate DA/NE secretion and elevated levels of DA/NE could delay the progress of PD, this work also enhances our understanding of the biological mechanism by which exercise prevents and alleviates PD.

In order to eliminate the influence of d-q axis coupling effect of permanent magnet synchronous linear motor, restrain the internal disturbance of permanent magnet synchronous linear motor (PMSLM) and suppress the thrust ripple of the motor, this paper analyses the coupling effect of d-q axis from the perspective of d-q axis mutual inductance and cross-coupling voltage of d-q axis. Based on that, the influence of the d-q axis coupling effect on the thrust ripple was studied quantitatively by establishing the motor model which inductance coupling effect and voltage coupling effect is considered. Moreover, the coupling effect of the control system is compensated by the voltage feedforward method. The simulation and experiment show that the vector control considering the coupling effect of the d-q axis improves the control accuracy of d-axis current and q-axis current, restrains the thrust ripple of the motor, and achieves high precision control requirements of the permanent magnet synchronous linear motor servo system.

Rollable prefabricated asphalt pavement technology consists of prefabricating and crimping the asphalt pavement in the factory. It can be laid on the pavement as carpets so that the constru...

The pathology Alzheimer&rsquo, s disease (AD) is associated with the self-assembly of amyloid-&beta, (A&beta, ) peptides into &beta, sheet enriched fibrillar aggregates. A promising treatment strategy is focused on the inhibition of amyloid fibrillization of A&beta, peptide. Fullerene C60 is proved to effectively inhibit A&beta, fibrillation while the poor water-solubility restricts its use as a biomedicine agent. In this work, we examined the interaction of fullerene C60 and water-soluble fullerenol C60(OH)6/C60(OH)12 (C60 carrying 6/12 hydroxyl groups) with preformed A&beta, 40/42 protofibrils by multiple molecular dynamics simulations. We found that when binding to the A&beta, 42 protofibril, C60, C60(OH)6 and C60(OH)12 exhibit distinct binding dynamics, binding sites and peptide interaction. The increased number of hydroxyl groups C60 carries leads to slower binding dynamics and weaker binding strength. Binding free energy analysis demonstrates that the C60/C60(OH)6 molecule primarily binds to the C-terminal residues 31&ndash, 41, whereas C60(OH)12 favors to bind to N-terminal residues 4&ndash, 14. The hydrophobic interaction plays a critical role in the interplay between A&beta, and all the three nanoparticles, and the &pi, stacking interaction gets weakened as C60 carries more hydroxyls. In addition, the C60(OH)6 molecule has high affinity to form hydrogen bonds with protein backbones. The binding behaviors of C60/C60(OH)6/C60(OH)12 to the A&beta, 40 protofibril resemble with those to A&beta, 42. Our work provides a detailed picture of fullerene/fullerenols binding to A&beta, protofibril, and is helpful to understand the underlying inhibitory mechanism.

As an indispensable process to identify the optimal treatment measures for bridge maintenance, the importance of decision-making techniques have been recently highlighted. In this paper, a multi-parameters project level bridge maintenance decision-making algorithm, conducted by the Probabilistic Neural Networks method, radial basis function method, and the Principal Component Analysis method, is investigated. A detailed study on the parameter selection, data classification, and prediction are performed by using the former two methods for the time-series index data, in terms of technical condition, average daily traffic, and sufficiency rating. The sub-item weight among different parameter indexes is calculated by the Principal Component Analysis method and evaluated by correlation evaluation. Besides, an overall evaluation model for the project level bridge maintenance decision-making is also suggested, in which the comprehensive state index model, target-based reliability model, the degradation rate factor model, and the life-cycle cost estimate and determination of maintenance time, are conducted. The optimal process is chosen and applied in three bridges as a case study. Results demonstrate that the optimal algorithm is preferable for bridge maintenance decision-making.

The capacitated vehicle routing problem (CVRP) has been proved to be NP complete problem. The CVRP is not just a purely academic construct, it has many applications in practice. In this work, a discrete invasive weed optimization algorithm (DIWO) is proposed to solve the capacitated vehicle routing problem. Adaptive mutation and crossover in the genetic operation process are introduced to ensure the diversity of the algorithm and prevent it from falling into a local optimal solution with premature convergence. We use real matrix encoding and construct a discretization process for the subgeneration in the parent generation region. An improved 2-Opt and exchange operations structure based on the property of the problem is proposed to construct the two-stage hybrid variable-domain search method, strengthening the capacity of the local and global search ability of the algorithms. Comparing the experimental simulation and the algorithm with literature for different scale benchmarks proves that the DIWO algorithm is simple, efficient, adaptable, and robust for discrete combinatorial optimization problems.

Increasing evidence suggests that the interaction of human islet amyloid polypeptide (hIAPP) with lipids may facilitate hIAPP aggregation and cause the death of pancreatic isletβ-cells. However, the detailed hIAPP-membrane interactions and the influences of lipid compositions are unclear. In this study, as a first step to understand the mechanism of membrane-mediated hIAPP aggregation, we investigate the binding behaviors of hIAPP monomer at zwitterionic palmitoyloleoyl-phosphatidylcholine (POPC) bilayer by performing atomistic molecular dynamics simulations. The results are compared with those of hIAPP at anionic palmitoyloleoyl-phosphatidylglycerol (POPG) bilayers. We find that the adsorption of hIAPP to POPC bilayer is mainly initiated from the C-terminal region and the peptide adopts a helical structure with multiple binding orientations, while the adsorption to POPG bilayer is mostly initiated from the N-terminal region and hIAPP displays one preferential binding orientation, with its hydrophobic residues exposed to water. hIAPP monomer inserts into POPC lipid bilayers more readily than into POPG bilayers. Peptide-lipid interaction analyses show that the different binding features of hIAPP at POPC and POPG bilayers are attributed to different magnitudes of electrostatic and hydrogen-bonding interactions with lipids. This study provides mechanistic insights into the different interaction behaviors of hIAPP with zwitterionic and anionic lipid bilayers.

In this paper, we introduce PhoenixMap, a visual analytics system to help analysts understand spatiotemporal distribution patterns and anomalies of many objects. It focuses on solving two VA challenges. First, visualizing the spatial distribution of many points under different categories especially when these points partially overlap with each other; Second, employing visual means to classify bird calls using deep learning CNN method. This PhoenixMap system can successfully help us understand the change and patterns of birds regions over many years.

TopoText is a context-preserving technique for visualizing text data for multi-scale spatial aggregates to gain insight into spatial phenomena. Conventional exploration requires users to navigate across multiple scales but only presents the information related to the current scale. This limitation potentially adds more steps of interaction and cognitive overload to the users. TopoText renders multi-scale aggregates into a single visual display combining novel text-based encoding and layout methods that draw labels along the boundary or filled within the aggregates. The text itself not only summarizes the semantics at each individual scale, but also indicates the spatial coverage of the aggregates and their underlying hierarchical relationships. We validate TopoText with both a user study as well as several application examples.

In this paper, the carbon emission factor is taken into account in the Location Routing Problem (LRP), and a multi-objective LRP model combining carbon emission with total cost is established. Due to the complexity of the proposed problem, a generality-oriented and emerging Multi-Objective Hyper Heuristic algorithm (MOHH) is proposed. In the framework of MOHH, the LRP related operates are constructed as the low level heuristics, and the different high level strategies are designed. Compared with the NSGA-II algorithm, the MOHH can better solve the multi-objective problem of LRP, and can quickly find the better solution, and achieve higher search efficiency and stability of the algorithm.

The pathology of type 2 diabetes mellitus is associated with the aggregation of human islet amyloid polypeptide (hIAPP) and aggregation-mediated membrane disruption. The interactions of hIAPP aggregates with lipid membrane, as well as the effects of pH and lipid composition at the atomic level, remain elusive. Herein, using molecular dynamics simulations, we investigate the interactions of hIAPP protofibrillar oligomers with lipids, and the membrane perturbation that they induce, when they are partially inserted in an anionic dipalmitoyl-phosphatidylglycerol (DPPG) membrane or a mixed dipalmitoyl-phosphatidylcholine (DPPC)/DPPG (7:3) lipid bilayer under acidic/neutral pH conditions. We observed that the tilt angles and insertion depths of the hIAPP protofibril are strongly correlated with the pH and lipid composition. At neutral pH, the tilt angle and insertion depth of hIAPP protofibrils at a DPPG bilayer reach ~52° and ~1.62 nm with respect to the membrane surface, while they become ~77° and ~1.75 nm at a mixed DPPC/DPPG membrane. The calculated tilt angle of hIAPP at DPPG membrane is consistent with a recent chiral sum frequency generation spectroscopic study. The acidic pH induces a smaller tilt angle of ~40° and a shallower insertion depth (~1.24 nm) of hIAPP at the DPPG membrane surface, mainly due to protonation of His18 near the turn region. These differences mainly result from a combination of distinct electrostatic, van der Waals, hydrogen bonding and salt-bridge interactions between hIAPP and lipid bilayers. The hIAPP-membrane interaction energy analysis reveals that besides charged residues K1, R11 and H18, aromatic residues Phe15 and Phe23 also exhibit strong interactions with lipid bilayers, revealing the crucial role of aromatic residues in stabilizing the membrane-bound hIAPP protofibrils. hIAPP-membrane interactions disturb the lipid ordering and the local bilayer thickness around the peptides. Our results provide atomic-level information of membrane interaction of hIAPP protofibrils, revealing pH-dependent and membrane-modulated hIAPP aggregation at the early stage.

Amphiphilic peptides can self-assemble into ordered nanostructures with different morphologies. However, the assembly mechanism and the structures of the early assemblies prior to nanostructure formation remain elusive. In this study, we investigated the oligomeric structures of two amphiphilic heptapeptides A6K and V6K by all-atom explicit-solvent replica-exchange molecular dynamics (REMD) simulations, and then examined the assembly dynamics of large aggregates by coarse-grained (CG) MD simulations. Our 200 ns REMD simulations show that A6K peptides predominantly adopt loosely packed disordered coil aggregates, whereas V6K peptides mostly assemble into compact β-sheet-rich conformations, consistent with the signal measured experimentally in aqueous solution. Well-organized β-sheet-rich conformations, albeit with low population, are also populated for V6K octamers, including bilayer β-sheets and β-barrels. These ordered β-sheet-rich conformations are observed for the first time for amphiphilic peptides. Our 10-μs CG-MD simulations on 200 peptide chains demonstrate that A6K and V6K peptides follow two different self-assembly processes, and the former form monolayer lamellas while the latter assemble into plate-like assemblies. CG-MD simulations also show that V6K peptides display higher assembly capability than A6K, in support of our all-atom REMD simulation results. Interpeptide interaction analyses reveal that the marked differences in oligomeric structures and assembly dynamics between A6K and V6K result from the subtle interplay of competition among hydrophobic, hydrogen-bonding, and electrostatic interactions of the two peptides. Our study provides structural and mechanistic insights into the initial self-assembly process of A6K and V6K at the molecular level.

In this article, we present a visual analytics system, SemanticPrism, which aims to analyze large-scale high-dimensional cyber security datasets containing logs of a million computers. SemanticPrism visualizes the data from three different perspectives: spatiotemporal distribution, overall temporal trends, and pixel-based IP (Internet Protocol) address blocks. With each perspective, we use semantic zooming to present more detailed information. The interlinked visualizations and multiple levels of detail allow us to detect unexpected changes taking place in different dimensions of the data and to identify potential anomalies in the network. After comparing our approach to other submissions, we outline potential paths for future improvement.

Research on the dynamics of single-membrane proteins remains underdeveloped due to the lack of proper approaches that can probe in real time the protein's insertion depth in lipid bilayers. Here we report a single-molecule visualization method to track both vertical insertion and lateral diffusion of membrane proteins in supported lipid bilayers by exploiting the surface-induced fluorescence attenuation (SIFA) of fluorophores. The attenuation follows a d−4 dependency, where d is the fluorophore-to-surface distance. The method is validated by observing the antimicrobial peptide LL-37 to transfer among five transmembrane positions: the surface, the upper leaflet, the centre, the lower leaflet and the bottom of the lipid bilayer. These results demonstrate the power of SIFA to study protein-membrane interactions and provide unprecedented in-depth understanding of molecular mechanisms of the insertion and translocation of membrane proteins., Assessing protein localization within lipid membranes is problematic. Here, the authors describe a single molecule visualization method based on surface-induced fluorescence attenuation (SIFA) to determine the insertion depth and lateral diffusion of a peptide in a lipid bilayer.

Alzheimer's disease (AD) is associated with the pathological self-assembly of amyloid-β (Aβ) peptides into β-sheet enriched fibrillar aggregates. Aβ dimers formed in the initial step of Aβ aggregation were reported to be the smallest toxic species. Inhibiting the formation of β-sheet-rich oligomers and fibrils is considered as the primary therapeutic strategy for AD. Previous studies reported that fullerene derivatives strongly inhibit Aβ fibrillation. However, the underlying inhibitory mechanism remains elusive. As a first step to understand fullerene-modulated full-length Aβ aggregation, we investigated the conformational ensemble of the Aβ1-42 dimer with and without 1,2-(dimethoxymethano)fullerene (DMF) - a more water-soluble fullerene derivative - by performing a 340 ns explicit-solvent replica exchange molecular dynamics simulation. Our simulations show that although disordered states are the most abundant conformations of the Aβ1-42 dimer, conformations containing diverse extended β-hairpins are also populated. The first most-populated β-hairpins involving residues L17-D23 and A30-V36 strongly resemble the engineered β-hairpin which is a building block of toxic Aβ oligomers. We find that the interaction of DMFs with Aβ peptides greatly impedes the formation of such β-hairpins and inter-peptide β-sheets. Binding energy analyses demonstrate that DMF preferentially binds not only to the central hydrophobic motif LVFFA of the Aβ peptide as suggested experimentally, but also to the aromatic residues including F4 and Y10 and the C-terminal hydrophobic region I31-V40. This study reveals a complete picture of the inhibitory mechanism of full-length Aβ1-42 aggregation by fullerenes, providing theoretical insights into the development of drug candidates against AD.