Quantitative prediction of multivalent ligand–receptor binding affinities for influenza, cholera, and anthrax inhibition

Multivalency achieves strong, yet reversible binding by the simultaneous formation of multiple weak bonds. It is a key interaction principle in biology and promising for the synthesis of high-affinity inhibitors of pathogens. We present a molecular model for the binding affinity of synthetic multivalent ligands onto multivalent receptors consisting of n receptor units arranged on a regular polygon. Ligands consist of a geometrically matching rigid polygonal core to which monovalent ligand units are attached via flexible linker polymers, closely mimicking existing experimental designs. The calculated binding affinities quantitatively agree with experimental studies for cholera toxin (n = 5) and anthrax receptor (n = 7) and allow to predict optimal core size and optimal linker length. Maximal binding affinity is achieved for a core that matches the receptor size and for linkers that have an equilibrium end-to-end distance that is slightly longer than the geometric separation between ligand core and receptor sites. Linkers that are longer than optimal are greatly preferable compared to shorter linkers. The angular steric restriction between ligand unit and linker polymer is shown to be a key parameter. We construct an enhancement diagram that quantifies the multivalent binding affinity compared to monovalent ligands. We conclude that multivalent ligands against influenza viral hemagglutinin (n = 3), cholera toxin (n = 5), and anthrax receptor (n = 7) can outperform monovalent ligands only for a monovalent ligand affinity that exceeds a core-size dependent threshold value. Thus, multivalent drug design needs to balance core size, linker length, as well as monovalent ligand unit affinity

Possible Local Spiral Counterparts to Compact Blue Galaxies at Intermediate Redshift

We identify nearby disk galaxies with optical structural parameters similar to those of intermediate-redshift compact blue galaxies. By comparing HI and optical emission-line widths, we show that the optical widths substantially underestimate the true kinematic widths of the local galaxies. By analogy, optical emission-line widths may underrepresent the masses of intermediate-z compact objects. For the nearby galaxies, the compact blue morphology is the result of tidally-triggered central star formation: we argue that interactions and minor mergers may cause apparently compact morphology at higher redshift.Comment: 5 pages, uses emulateapj5 and psfig. To appear in ApJ

Hydration effects turn a highly stretched polymer from an entropic into an energetic spring

Polyethylene glycol (PEG) is a structurally simple and nontoxic water-soluble polymer that is widely used in medical and pharmaceutical applications as molecular linker and spacer. In such applications, PEG’s elastic response against conformational deformations is key to its function. According to text-book knowledge, a polymer reacts to the stretching of its end-to-end separation by a decrease in entropy that is due to the reduction of available conformations, which is why polymers are commonly called entropic springs. By a combination of single-molecule force spectroscopy experiments with molecular dynamics simulations in explicit water, we show that entropic hydration effects almost exactly compensate the chain conformational entropy loss at high stretching. Our simulations reveal that this entropic compensation is due to the stretching-induced release of water molecules that in the relaxed state form double hydrogen bonds with PEG. As a consequence, the stretching response of PEG is predominantly of energetic, not of entropic, origin at high forces and caused by hydration effects, while PEG backbone deformations only play a minor role. These findings demonstrate the importance of hydration for the mechanics of macromolecules and constitute a case example that sheds light on the antagonistic interplay of conformational and hydration degrees of freedom

The Annual Economic Survey of Federal Gulf Shrimp Permit Holders: Report on the Design, Implementation, and Descriptive Results for 2006

This technical memorandum documents the design, implementation, data preparation, and descriptive results for the 2006 Annual Economic Survey of Federal Gulf Shrimp Permit Holders. The data collection was designed by the NOAA Fisheries Southeast Fisheries Science Center Social Science Research Group to track the financial and economic status and performance by vessels holding a federal moratorium permit for harvesting shrimp in the Gulf of Mexico. A two page, self-administered mail survey collected total annual costs broken out into seven categories and auxiliary economic data. In May 2007, 580 vessels were randomly selected, stratified by state, from a preliminary population of 1,709 vessels with federal permits to shrimp in offshore waters of the Gulf of Mexico. The survey was implemented during the rest of 2007. After many reminder and verification phone calls, 509 surveys were deemed complete, for an ineligibility-adjusted response rate of 90.7%. The linking of each individual vessel’s cost data to its revenue data from a different data collection was imperfect, and hence the final number of observations used in the analyses is 484. Based on various measures and tests of validity throughout the technical memorandum, the quality of the data is high. The results are presented in a standardized table format, linking vessel characteristics and operations to simple balance sheet, cash flow, and income statements. In the text, results are discussed for the total fleet, the Gulf shrimp fleet, the active Gulf shrimp fleet, and the inactive Gulf shrimp fleet. Additional results for shrimp vessels grouped by state, by vessel characteristics, by landings volume, and by ownership structure are available in the appendices. The general conclusion of this report is that the financial and economic situation is bleak for the average vessels in most of the categories that were evaluated. With few exceptions, cash flow for the average vessel is positive while the net revenue from operations and the “profit” are negative. With negative net revenue from operations, the economic return for average shrimp vessels is less than zero. Only with the help of government payments does the average owner just about break even. In the short-term, this will discourage any new investments in the industry. The financial situation in 2006, especially if it endures over multiple years, also is economically unsustainable for the average established business. Vessels in the active and inactive Gulf shrimp fleet are, on average, 69 feet long, weigh 105 gross tons, are powered by 505 hp motor(s), and are 23 years old. Three-quarters of the vessels have steel hulls and 59% use a freezer for refrigeration. The average market value of these vessels was $175,149 in 2006, about a hundred-thousand dollars less than the average original purchase price. The outstanding loans averaged$91,955, leading to an average owner equity of $83,194. Based on the sample, 85 owner-operated. On average, these vessels burned 52,931 gallons of fuel, landed 101,268 pounds of shrimp, and received$2.47 per pound of shrimp. Non-shrimp landings added less than 1% to cash flow, indicating that the federal Gulf shrimp fishery is very specialized. The average total cash outflow was $243,415 of which$108,775 was due to fuel expenses alone. The expenses for hired crew and captains were on average $54,866 which indicates the importance of the industry as a source of wage income. The resulting average net cash flow is$16,225 but has a large standard deviation. For the population of active Gulf shrimp vessels we can state with 95% certainty that the average net cash flow was between $9,500 and$23,000 in 2006. The median net cash flow was $11,843. Based on the income statement for active Gulf shrimp vessels, the average fixed costs accounted for just under a quarter of operating expenses (23.1 The average labor contribution (as captain) of an owner-operator is estimated at about$19,800. The average net revenue from operations is negative $7,429, and is statistically different and less than zero in spite of a large standard deviation. The economic return to Gulf shrimping is negative 4$13,662, leads to an average loss before taxes of $907 for the vessel owners. The confidence interval of this value straddles zero, so we cannot reject, with 95 The average inactive Gulf shrimp vessel is generally of a smaller scale than the average active vessel. Inactive vessels are physically smaller, are valued much lower, and are less dependent on loans. Fixed costs account for nearly three quarters of the total operating expenses of$11,926, and only 6% of these vessels have hull insurance. With an average net cash flow of negative $7,537, the inactive Gulf shrimp fleet has a major liquidity problem. On average, net revenue from operations is negative$11,396, which amounts to a negative 15% economic return, and owners lose $9,381 on their vessels before taxes. To sustain such losses and especially to survive the negative cash flow, many of the owners must be subsidizing their shrimp vessels with the help of other income or wealth sources or are drawing down their equity. Active Gulf shrimp vessels in all states but Texas exhibited negative returns. The Alabama and Mississippi fleets have the highest assets (vessel values), on average, yet they generate zero cash flow and negative$32,224 net revenue from operations. Due to their high (loan) leverage ratio the negative 11% economic return is amplified into a negative 21% return on equity. In contrast, for Texas vessels, which actually have the highest leverage ratio among the states, a 1% economic return is amplified into a 13% return on equity. From a financial perspective, the average Florida and Louisiana vessels conform roughly to the overall average of the active Gulf shrimp fleet. It should be noted that these results are averages and hence hide the variation that clearly exists within all fleets and all categories. Although the financial situation for the average vessel is bleak, some vessels are profitable. (PDF contains 101 pages

The effect of temperature on single-polypeptide adsorption

The hydrophobic attraction (HA) is believed to be one of the main driving forces for protein folding. Understanding its temperature dependence promises a deeper understanding of protein folding. Herein, we present an approach to investigate the HA with a combined experimental and simulation approach, which is complementary to previous studies on the temperature dependence of the solvation of small hydrophobic spherical particles. We determine the temperature dependence of the free-energy change and detachment length upon desorption of single polypeptides from hydrophobic substrates in aqueous environment. Both the atomic force microscopy (AFM) based experiments and the molecular dynamics (MD) simulations show only a weak dependence of the free energy change on temperature. In fact, depending on the substrate, we find a maximum or a minimum in the temperature-dependent free energy change, meaning that the entropy increases or decreases with temperature for different substrates. These observations are in contrast to the solvation of small hydrophobic particles and can be rationalized by a compensation mechanism between the various contributions to the desorption force. On the one hand this is reminiscent of the protein folding process, where large entropic and enthalpic contributions compensate each other to result in a small free energy difference between the folded and unfolded state. On the other hand, the protein folding process shows much stronger temperature dependence, pointing to a fundamental difference between protein folding and adsorption. Nevertheless such temperature dependent single molecule desorption studies open large possibilities to study equilibrium and non-equilibrium processes dominated by the hydrophobic attraction

Force Response of Polypeptide Chains from Water-Explicit MD Simulations

Using molecular dynamics simulations in explicit water, the force–extension relations for the five homopeptides polyglycine, polyalanine, polyasparagine, poly(glutamic acid), and polylysine are investigated. From simulations in the low-force regime the Kuhn length is determined, from simulations in the high-force regime the equilibrium contour length and the linear and nonlinear stretching moduli, which agree well with quantum-chemical density-functional theory calculations, are determined. All these parameters vary considerably between the different polypeptides. The augmented inhomogeneous partially freely rotating chain (iPFRC) model, which accounts for side-chain interactions and restricted dihedral rotation, is demonstrated to describe the simulated force–extension relations very well. We present a quantitative comparison between published experimental single-molecule force–extension curves for different polypeptides with simulation and model predictions. The thermodynamic stretching properties of polypeptides are investigated by decomposition of the stretching free energy into energetic and entropic contributions

Markarian 421's Unusual Satellite Galaxy

We present Hubble Space Telescope (HST) imagery and photometry of the active galaxy Markarian 421 and its companion galaxy 14 arcsec to the ENE. The HST images indicate that the companion is a morphological spiral rather than elliptical as previous ground--based imaging has concluded. The companion has a bright, compact nucleus, appearing unresolved in the HST images. This is suggestive of Seyfert activity, or possibly a highly luminous compact star cluster. We also report the results of high dynamic range long-slit spectroscopy with the slit placed to extend across both galaxies and nuclei. We detect no emission lines in the companion nucleus, though there is evidence for recent star formation. Velocities derived from a number of absorption lines visible in both galaxies indicate that the two systems are probably tidally bound and thus in close physical proximity. Using the measured relative velocities, we derive a lower limit on the MKN 421 mass within the companion orbit (R \sim 10 kpc) of 5.9 \times 10^{11} solar masses, and a mass-to-light ratio of >= 17. Our spectroscopy also shows for the first time the presence of H\alpha and [NII] emission lines from the nucleus of MKN 421, providing another example of the appearance of new emission features in the previously featureless spectrum of a classical BL Lac object. We see both broad and narrow line emission, with a velocity dispersion of several thousand km s^{-1} evident in the broad lines.Comment: LaTeX (aaspp4 style), 28 pages, 8 figures, to appear in AJ. Revised text from ref. comments; new & modified figures; new photometry included; minor corrections of typos. Color version of Fig. 1 to appear in Feb. 2000 Sky & Telescop

On the relationship between peptide adsorption resistance and surface contact angle: a combined experimental and simulation single-molecule study

The force-induced desorption of single peptide chains from mixed OH/CH3-terminated self-assembled monolayers is studied in closely matched molecular dynamics simulations and atomic force microscopy experiments with the goal to gain microscopic understanding of the transition between peptide adsorption and adsorption resistance as the surface contact angle is varied. In both simulations and experiments, the surfaces become adsorption resistant against hydrophilic as well as hydrophobic peptides when their contact angle decreases below θ ≈ 50°-60°, thus confirming the so-called Berg limit established in the context of protein and cell adsorption. Entropy/enthalpy decomposition of the simulation results reveals that the key discriminator between the adsorption of different residues on a hydrophobic monolayer is of entropic nature and thus is suggested to be linked to the hydrophobic effect. By pushing a polyalanine peptide onto a polar surface, simulations reveal that the peptide adsorption resistance is caused by the strongly bound water hydration layer and characterized by the simultaneous gain of both total entropy in the system and total number of hydrogen bonds between water, peptide, and surface. This mechanistic insight into peptide adsorption resistance might help to refine design principles for anti-fouling surfaces