337 research outputs found
Enhancing sampling of water rehydration upon ligand binding using variants of grand canonical Monte Carlo
No full textWater plays an important role in mediating protein-ligand interactions. Water rearrangement upon a ligand binding or modification can be very slow and beyond typical timescales used in molecular dynamics (MD) simulations. Thus, inadequate sampling of slow water motions in MD simulations often impairs the accuracy of the accuracy of ligand binding free energy calculations. Previous studies suggest grand canonical Monte Carlo (GCMC) outperforms normal MD simulations for water sampling, thus GCMC has been applied to help improve the accuracy of ligand binding free energy calculations. However, in prior work we observed protein and/or ligand motions impaired how well GCMC performs at water rehydration, suggesting more work is needed to improve this method to handle water sampling. In this work, we applied GCMC in 21 protein-ligand systems to assess the performance of GCMC for rehydrating buried water sites. While our results show that GCMC can rapidly rehydrate all selected water sites for most systems, it fails in five systems. In most failed systems, we observe protein/ligand motions, which occur in the absence of water, combine to close water sites and block instantaneous GCMC water insertion moves. For these five failed systems, we both extended our GCMC simulations and tested a new technique named grand canonical nonequilibrium candidate Monte Carlo (GCNCMC). GCNCMC combines GCMC with the nonequilibrium candidate Monte Carlo (NCMC) sampling technique to improve the probability of a successful water insertion/deletion. Our results show that GCNCMC and extended GCMC can rehydrate all target water sites for three of the five problematic systems and GCNCMC is more efficient than GCMC in two out of the three systems. In one system, only GCNCMC can rehydrate all target water sites, while GCMC fails. Both GCNCMC and GCMC fail in one system. This work suggests this new GCNCMC method is promising for water rehydration especially when protein/ligand motions may block water insertion/removal.</p
Enhanced grand canonical sampling of occluded water sites using nonequilibrium candidate Monte Carlo
No full textWater molecules play a key role in many biomolecular systems, particularly when bound at protein-ligand interfaces. However, molecular simulation studies on such systems are hampered by the relatively long time scales over which water exchange between a protein and solvent takes place. Grand canonical Monte Carlo (GCMC) is a simulation technique that avoids this issue by attempting the insertion and deletion of water molecules within a given structure. The approach is constrained by low acceptance probabilities for insertions in congested systems, however. To address this issue, here, we combine GCMC with nonequilibium candidate Monte Carlo (NCMC) to yield a method that we refer to as grand canonical nonequilibrium candidate Monte Carlo (GCNCMC), in which the water insertions and deletions are carried out in a gradual, nonequilibrium fashion. We validate this new approach by comparing GCNCMC and GCMC simulations of bulk water and three protein binding sites. We find that not only is the efficiency of the water sampling improved by GCNCMC but that it also results in increased sampling of ligand conformations in a protein binding site, revealing new water-mediated ligand-binding geometries that are not observed using alternative enhanced sampling techniques. </p
Synthesis of (3S,3S',4S,4S')-1,1'-ethylenedipyrrolidine-3,3',4,4'-tetraol and related diamino diols: donor-acceptor hydrogen-bonding motifs of the C-2 symmetric 3,4-dihydroxypyrrolidine unit
No full textEnantiopure 1,1'-ethylenedipyrrolidines possessing 3,4-disubstitution have been prepared from esters of L-(+)-tartaric acid. Although diacylation routes via the diacetoxypyrrolidin-2,5-diones were problematic, N,N-dialkylation protocols proved to be reliable and led to the synthesis of(3S,3S',4S,4S')-1,1'-ethylenedipyrrolidine-3,3',4,4'-tetraoi, (3R,3'S,4R,4'S)-3,4-diamino-1,1'-ethylenedipyrrolidine-3',4'-diol and (3R,3'R,4S,4'S)-3,3'-diamino-1,1'-ethylenedipyrrolidine-4,4'-diol. The tetraol possesses a crystal structure that exhibits an unusual zig-zag intermolecular pattern comprising a network of hydrogen bonds involving the terminal hydroxyl groups and a nitrogen atom of one of the pyrrolidine rings
The impact of structural changes on the actuation of polypyrroles
No full textA new non-contact method for characterizing the time-dependent mechanical performance of electro-active polymer films has been developed and is described in detail. We first illustrate our new measuring technique by investigating the impact of film thickness on the actuation performance of polypyrrole. Our method is simple to perform and serves as a valuable tool for studying the long term stability and operational failure of the films, the effects of synthesis conditions and for the optimization of actuator performance.
We have used our technique to investigate the impact that structural changes, such as crosslinking, have on the actuation of polypyrroles. An understanding of this relationship is necessary if forms of polypyrrole are to be produced that are capable of greater movement, operating speeds, in service lifetimes and force generation. In order to do this we have developed a logical synthetic strategy (blocking approach) which allows us to change the degree of crosslinking in electro-synthesised polypyrrole. Using our blocking approach we have been able to show the impact that structural changes make on the actuation performance of polypyrroles.
We have shown that it is possible to monitor crosslinking and branching changes in polypyrroles indirectly using the irreversible expansion of these films. Our measurements are a form of “dynamic swelling study” and are analogous with solvent swelling studies used in the polymer industry for monitoring cross-linking changes.
The irreversible expansion of polypyrrole films has been used to investigate the effects that polymerization potential has upon the levels of cross-linking and branching. We go on to identify the optimal conditions for producing the maximum expansion, strain and strain rate for PPy(DBS). In addition, we have used instrumented indentation as a secondary method for monitoring crosslinking changes. This has provided information that is consistent with those revealed by changes in the irreversible expansion of the polymer.
Finally we present an in-depth theoretical discussion of how elemental analysis could be used as a more direct way to quantitatively determine the levels of crosslinking within polypyrroles.
This work represents the first study of its kind aimed at understanding the impact that crosslinking and branching has upon the actuation performance of polypyrroles. As a result we are closer to being able to synthesize polypyrroles with improved actuator properties such as greater strains and strain rates
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No full textCharacterization of Long-period Ship Wave Loading and Vessel Speed for Risk Assessment for Rock Groyne Designs via Extreme Value Analysis
No full textDuring the last two decades, increasing vessel size in major German estuaries has led to the significant change of the local loading regime i.e. increased importance of ship-induced waves and currents. As a consequence, the intensity of ship-induced loads has increased considerably, resulting in damage to rock structures such as revetments, training walls, and groynes. Research into the causes of rock structure deterioration by the Federal Waterways Engineering and Research Institute (BAW) has shown that for large ships in relatively narrow waterways, the long-period primary ship wave loading has become the most prescient factor for rock structure damage. Looking into the future, it can be expected that the increase in the vessel dimensions will lead to an increase in the ship-wave loading. For this reason, analysing long-term changing trends of long-period ship waves and vessel speed to understand the wave-structure interaction is of significant importance. In this study, the stochastic characterization of long-period primary wave height, drawdown, and speed of the vessel through the water at Juelssand in the Lower Elbe Estuary was analysed via extreme value analysis and copula modeling, and the bivariate return periods were calculated. The one-parameter bivariate copula was utilized to analyse the data. The dependence pattern between the variables was investigated using five parametric copula families: Gaussian, Gumbel, Clayton, Frank, and student's t.Accepted Author ManuscriptHydraulic Structures and Flood Ris
Washington\u27s Electronic Authentication Act: Eliminating Legal Uncertainties Through Default Rules
No full textThis article responds to C. Bradford Biddle’s Legislating Market Winners: Digital Signature Laws and the Electronic Commerce Marketplace. Using Washington’s Electronic Authentication Act as a model, the author rejects Biddle’s arguments against digital signature legislation. The problem of “legislating market winners” through digital signature legislation can be avoided, according to the author, by creating default background rules that can be avoided by private contract. Nevertheless, the Washington Act could be improved by amendment to strengthen consumer protection against fraudulent digital signatures and related problems of e-commerce
Sex differences in space use, body condition and survivorship during the breeding season in the Namaqua rock mouse, Aethomys namaquensis
No full textAlthough the determinants of sex differences in territoriality have been addressed for many species, the consequences of such differences in space use, particularly in southern hemisphere taxa, have received limited attention. The Namaqua rock mouse, Aethomys namaquensis, is a medium-sized, omnivorous, nocturnal murid with a wide distribution throughout southern Africa. Sex differences in space use behaviour were found: female captures were described by non-overlapping contiguous areas, whereas males were caught over 50% larger areas that overlapped spatially and temporally. Movements during breeding were characteristic of scramble-competition polygyny: a transient influx of non-resident males (coinciding with an increase in perforate females) skews the sex ratio towards males early in the breeding season. Whereas female condition improved with time, male body condition declined significantly over the breeding period (r262 = 0.134, P = 0.002) and males had lower persistence in the trappable population. This study may therefore document a link between mobility (associated with a polygynous mating system) and reduced male survivorship and body condition for this murine rodent
Effects of promoters on catalytic activity and carbon deposition of Ni/gamma-Al2O3 catalysts in CO2 reforming of CH4
No full textCatalytic reforming of methane with carbon dioxide was studied in a fixed-bed reactor using unpromoted and promoted Ni/gamma-Al2O3 catalysts. The effects of promoters, such as alkali metal oxide (Na2O), alkaline-earth metal oxides (MgO, CaO) and rare-earth metal oxides (La2O3, CeO2), on the catalytic activity and stability in terms of coking resistance and coke reactivity were systematically examined. CaO-, La2O3- and CeO2-promoted Ni/gamma-Al2O3 catalysts exhibited higher stability whereas MgO- and Na2O-promoted catalysts demonstrated lower activity and significant deactivation. Metal-oxide promoters (Na2O, MgO, La2O3, and CeO2) suppressed the carbon deposition, primarily due to the enhanced basicities of the supports and highly reactive carbon species formed during the reaction. In contrast, CaO increased the carbon deposition; however, it promoted the carbon reactivity. (C) 2000 Society of Chemical Industry
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