Revealing binding selectivity of ligands toward murine double minute 2 and murine double minute X based on molecular dynamics simulations and binding free energy calculations

Abstract

It is well known that the interactions of p53 with murine double minute 2 and murine double minute X, namely MDM2 and MDMX, have been significant targets of efficient anti-cancer drug design. In this study, molecular dynamics (MD) simulations, principal component (PC) analysis and binding free energy calculations are combined to recognize binding selectivity of three ligands to MDM2 and MDMX. The binding free energies were estimated by using molecular mechanics generalized Born surface area (MM-GBSA) method and the obtained results display that the increase in the binding enthalpy of three ligands to MDM2 relative to MDMX mainly drives the binding selectivity of them toward MDM2 and MDMX. The information obtained from PC analysis shows that the associations of ligands exert important impacts on internal dynamics of MDM2 and MDMX. Meanwhile, the calculations of residue-based free energy decomposition not only identify the hot interaction spots of ligands with MDM2 and MDMX, but also show the residues (L54, M53), (Y67, Y66), (V93, V92), (H96, P95), (I99, I98) and (Y100, Y99) in (MDM2, MDMX) are responsible for most contributions to the binding selectivity of three ligands toward MDM2 and MDMX. It is believed that this work can provide useful information for design of highly selective and dual inhibitors targeting MDM2 and MDMX.

Communicated by Ramaswamy H. Sarma     

Epidemics of Rhizoctonia Root Rot in Association with Biological and Physicochemical Properties of Field Soil in Bean Crops

During two growing seasons (2008 and 2009), the associations of Rhizoctonia root rot (RRR) with a number of soil properties were determined at different growth stages in 122 commercial bean fields in Zanjan, Iran. Mean RRR incidence at a level of 4–25% sand content was lower than that at 45–65% level. Damage by fly puparia had no significant effect on RRR incidence and occurrence. A greater RRR incidence was detected in field soils treated with fungicides compared with non‐treated soils. A lower RRR incidence was associated with the highest level of soil organic matter (1.2–1.8) compared with the lowest level, 0.4–0.8. The highest RRR incidence corresponded with no rhizobial nodulation compared with highly nodulated bean roots. RRR incidence was negatively correlated with soil silt and organic matter content at R6–7 and R9 growth stages. RRR‐affected fields were recognized with a greater soil pH (V3) and sand content (R9), and a lower silt (R9) and organic matter content (R6–7 and R9) in comparison with RRR‐free fields. Loadings and linear regressions between RRR incidence and principal component scores indicated that the most effective soil characteristic linked to the disease was silt at V3, sand at R6–7 and organic matter at R9 stage. This new epidemiological information extends our knowledge of the bean–RRR–soil interaction on a regional basis.     

Spawning and Brood Defense of Smallmouth Bass Under the Process of Invasion into a Novel Habitat

Smallmouth bass, Micropterus dolomieu, known as one of the world's most disastrous invasive species, was introduced into Lake Aoki, central Japan in the last 10 years and is of concern for the conservation of the native biodiversity. We investigated spawning and brood defense under novel conditions to devise measures to eradicate a local population of this species. Compared to their native habitat, the size distribution of nesting males was less skewed to the right in this invasive population but rather a skewed normal distribution probably due to prevention of younger cohorts entering the nesting stock. The number of offspring deposited in nests was not positively related to the size of the nesting male. These observations imply that a shortage of suitable nest sites leads to an escalation in male–male competition, followed by a relaxation of female mate choice based on male size. Further, when presented with a model of a potential predator of the offspring, nesting males reacted individually and the intensity of site tenacity was independent of the male size. We propose that the removal of cover accompanied by the use of native predators of young bass can effectively decelerate the expansion of invasive smallmouth bass.     

Sexually differentiated flight responses of the Mexican bean beetle to larval and adult nutrition

Summary Flight of male and female Mexican bean beetle adults was examined in laboratory tests. The experimental design made it possible to examine flight behavior not only with respect to different types of hosts (young vs senescent common bean foliage) but also with respect to effects due to their utilization during particular stages of beetle development. The median flight time of males was significantly affected by the adult host, but not by the juvenile host; whereas, the median flight time of females tended to be more affected by the juvenile than by the adult host. These different effects of hosts on the flight times of males and females resulted in sexual dimorphism in flight when the sexes were fed senescent foliage as adults. Although age significantly affected the flight time of both males and females, the reproductive status of females did not affect their flight times. The significance of these results are discussed with respect to the influence of the nutritional complexity of habitats on life history strategies and population dynamics.     

Relationship between iron chlorosis and alkalinity in Zea mays

Mengel, K. and Geurtzen, G. 1988. Relationship between iron chlorosis and alkalinity in Zea mays . - Physiol. Plant. 72: 460–465.
Maize ( Zea mays L. cv. Anjou 21) grown in nutrient solution with Fe-EDTA and with nitrate as the sole nitrogen source showed typical Fe-chlorosis symptoms after a growth period of 14–21 days. Alkalinity in roots, stems and leaves of the chlorotic plants was high. Transferring the chlorotic plants from the nitrate-containing nutrient solution to a solution of (NH₄)₂SO₄ resulted in a regreening of leaves within 2–3 days which was associated with a decrease in solution pH, a decrease in alkalinity of plant parts, a translocation of Fe from roots to tops and a release of Fe into the outer solution. Similar effects were obtained when Fe chlorotic plants were transferred to a dilute HO solution with pH 3.5.
Spraying chlorotic leaves with indoleacetic acid or with fusicoccin led also to a regreening of leaves without having a major effect on leaf alkalinity.
Interpretation of the experimental results is based on the assumption that nitrate as sole N source leads to a high pH level in the apoplast resulting in the precipitation of Fe compounds, probably Fe oxide hydrate. Ammonium nutrition has the reverse effect since it lowers the apoplast pH and this can result in the dissolution of Fe compounds. Application of indoleacetic acid as well as fusicoccin supposedly stimulates the proton pumps in the plasmalemma of the leaf tissue. The resulting decrease in apoplast leaf pH in the microenvironment also leads to a dissolution of Fe compounds in the apoplast and thus promotes the uptake of Fe by the symplasm.     

Role of carboxylate in the nitrogen metabolism of plants from different natural habitats

The carboxylate and organic nitrogen content was studied in plants from 5 different habitats in Austria in order to determine both the form of nitrogen utilized by the plants and the preferential site of nitrate reduction within the plant, if nitrate is the predominant nitrogen form and is reduced mainly in the shoots, the ratio between carboxylate and organic nitrogen should be about 1. Ratios less then 1 would indicate either participation of root reduction, transport of carboxylate from shoots to roots or ammonium/ammonia nutrition.
In the plants investigated, the lowest ratios were found in a bog, where ammonium is usually the predominant nitrogen form. Species from a xerophytic and a nutrient-rich habitat, as well as from a carr, showed higher organic nitrogen values. Highest contents of carboxylate and organic nitrogen were found in halophytes from the area around the take Neusiedlersee. As additional bicarbonate uptake is known to occur at these sites, accumulation of carboxylate here may not he related to nitrate reduction alone.
The relationship between the carboxylate/organic nitrogen ratio and N indicator values revealed the same pattern of differences in the plant species, indicating that the determination of these values could give information of ecophysiological characteristics of, and differences between, plant species from various habitats.     

Nutrition and growth of birch seedlings at varied relative phosphorus addition rates

Birch ( Betula pendula Roth.) was investigated under steady state nutrition and growth at different relative addition rates of phosphorus (R_p). Phosphorus deficiency symptoms appeared on the leaves when the internal phosphorus concentration decreased, but disappeared again under steady state nutrition, independent of the stress level. The increased root/shoot ratio and the exploratory type of root systems developed during the adjustment stage remained under steady state conditions. At nonoptimum and close to optimum relative addition rates, independent of the rate, the phosphorus concentration of the culture solution did not exceed 2 μmol dm⁻³ and was generally < 1 μmol dm⁻³ immediately after phosphorus additions. The phosphorus concentration just before additions was generally < 0.5 μmol dm⁻³. The nutrition/growth relationships were similar to those for nitrogen, with relative growth rate (R_g) closely related to the R_p applied and with a strong linear relationship between internal phosphorus concentration and R_g. Regression was much steeper than that for nitrogen. The slope of the optimum nutrition was attained at a lower phosphorus weight proportion to nitrogen (8–10 P: 100 N) than previously estimated (= 13 P: 100 N), but a higher relative phosphorus requirement was observed under stress conditions. Birch seedlings had a strong tendency to consume phosphorus in excess of immediate requirements with a small effect on growth above optimum. This resulted in rapidly decreasing phosphorus productivity (P_p, growth rate per unit of phosphorus) with increasing internal phosphorus concentrations above optimum.     

Inhibition of photosynthesis and transpiration in relation to mercury-induced root damage in spruce seedlings

Spruce seedlings [ Picea abies (L.) Karst.] were exposed in nutrient solutions to a range of concentrations of HgCl₂ and CH₃HgCl for 7 weeks. The mineral, chlorophyll and water contents of the needles, and dry weights of root and needles were then estimated. The rates of photosynthesis, transpiration and dark respiration of the intact plants were determined using a Li-cor portable photosynthesis-measuring system. CO₂ uptake decreased as the supply of both forms of Hg increased. Rates of transpiration were significantly reduced only after exposure to CH₃HgCl. Similar concentrations of Hg were found in needles independent of the form of Hg supplied. Decreased rates of CO₂ uptake at 100 n M HgCl₂ and 1 n M CH₃HgCl could be explained by lower levels of chlorophyll, and by lower levels of chlorophyll and closed stomata at all other CH₃HgCl concentrations. Only at 1000 n M HgCl₂ were other photosynthetic parameters affected.
Decreased rates of transpiration and the lower chlorophyll levels in the needles did not appear to be due to the direct action of Hg, but rather to root damage that leads to a decrease in water supply and nutrient levels in the needles.