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611.
《Bioorganic & medicinal chemistry》2020,28(1):115143
Drug discovery is increasingly tackling challenging protein binding sites regarding molecular recognition and druggability, including shallow and solvent-exposed protein-protein interaction interfaces. Macrocycles are emerging as promising chemotypes to modulate such sites. Despite their chemical complexity, macrocycles comprise important drugs and offer advantages compared to non-cyclic analogs, hence the recent impetus in the medicinal chemistry of macrocycles. Elaboration of macrocycles, or constituent fragments, can strongly benefit from knowledge of their binding mode to a target. When such information from X-ray crystallography is elusive, computational docking can provide working models. However, few studies have explored docking protocols for macrocycles, since conventional docking methods struggle with the conformational complexity of macrocycles, and also potentially with the shallower topology of their binding sites. Indeed, macrocycle binding mode prediction with the mainstream docking software GOLD has hardly been explored. Here, we present an in-depth study of macrocycle docking with GOLD and the ChemPLP scores. First, we summarize the thorough curation of a test set of 41 protein-macrocycle X-ray structures, raising the issue of lattice contacts with such systems. Rigid docking of the known bioactive conformers was successful (three top ranked poses) for 92.7% of the systems, in absence of crystallographic waters. Thus, without conformational search issues, scoring performed well. However, docking success dropped to 29.3% with the GOLD built-in conformational search. Yet, the success rate doubled to 58.5% when GOLD was supplied with extensive conformer ensembles docked rigidly. The reasons for failure, sampling or scoring, were analyzed, exemplified with particular cases. Overall, binding mode prediction of macrocycles remains challenging, but can be much improved with tailored protocols. The analysis of the interplay between conformational sampling and docking will be relevant to the prospective modelling of macrocycles in general. 相似文献
612.
SLOWER TEMPO OF MICROEVOLUTION IN ISLAND BIRDS: IMPLICATIONS FOR CONSERVATION BIOLOGY 总被引:1,自引:0,他引:1
Shane D. Wright Len N. Gillman Howard A. Ross D. Jeanette Keeling 《Evolution; international journal of organic evolution》2009,63(9):2275-2287
Whether microevolution on small islands differs from that on larger landmasses is a key question in biology with substantial implications for species conservation. However, due to the difficulties faced in producing adequately replicated samples and in controlling for confounding variables, prior attempts to examine evolutionary questions relating to habitat area and population size have produced equivocal results. Here we show, using experimental design criteria that reduce the potential for such confounding, that bird species on larger landmasses have higher rates of molecular evolution. The study involves a global dataset of 48 independent contrasts for the cytochrome b gene encompassing all possible paired sister species comparisons (from seven orders and 17 families) that were available at the time of dataset assembly. A more rapid evolutionary tempo in larger areas has important ramifications for biodiversity conservation because it indicates a new imperative, beyond that of simply maintaining preexisting genetic diversity, for securing large areas for threatened species. This result suggests that the trend of confining species to limited refugia is likely to be slowing the tempo of microevolution. That effect might constrain the potential for adaptive shifts in response to changing environments such as those associated with global warming. 相似文献
613.
Rodrigo Garza-Galindo Ofelia Morton-Bermea Elizabeth Hernández-Álvarez Sara L. Ordoñez-Godínez Omar Amador-Muñoz Laura Beramendi-Orosco 《人类与生态风险评估》2020,26(5):1164-1174
AbstractPlatinum (Pt) concentrations in PM2.5 were evaluated by means of inductively coupled plasma mass spectrometry (ICP-MS) to evaluate the spatial and temporal behavior and to assess trends. Samples were taken from five representative sites in the Mexico City Metropolitan Area (MCMA): Tlalnepantla-northwest (NW), San Agustin-northeast (NE), La Merced -center (C), Coyoacan-southwest (SW), and Universidad Autonoma Metropolitana Iztapalapa-southeast (SE). Under three weather conditions: dry warm (DW-April), rainy (R-August), and dry cold (DC-November) in 2013. We found that the PM2.5 median mass concentration was 24?μg m?3?±?15?μg m?3 while Pt concentration was 55?pg m?3?±?15?pg m?3 (median, interquartile range). Seasonal trend was identified: the concentrations decreased significantly in the following order DC?>?R>DW. No spatial distribution was observed. Interestingly, among other meteorically parameters, wind intensity resulted to be the major factor for the dispersion of Pt in PM2.5 in MCMA. Furthermore, we found that Pt concentrations increased significantly by 19.6% between 2011 and 2013. Regardless of the increase in Pt, carbon monoxide (CO) levels decreased opposite to a rise in vehicular fleet. These results urge for environment public policies that address the upward tendency of Pt levels especially in urban areas. 相似文献
614.
《Journal of molecular biology》2023,435(2):167915
Effective proteome homeostasis is key to cellular and organismal survival, and cells therefore contain efficient quality control systems to monitor and remove potentially toxic misfolded proteins. Such general protein quality control to a large extent relies on the efficient and robust delivery of misfolded or unfolded proteins to the ubiquitin–proteasome system. This is achieved via recognition of so-called degradation motifs—degrons—that are assumed to become exposed as a result of protein misfolding. Despite their importance, the nature and sequence properties of quality-control degrons remain elusive. Here, we have used data from a yeast-based screen of 23,600 17-residue peptides to build a predictor of quality-control degrons. The resulting model, QCDPred (Quality Control Degron Prediction), achieves good accuracy using only the sequence composition of the peptides as input. Our analysis reveals that strong degrons are enriched in hydrophobic amino acids and depleted in negatively charged amino acids, in line with the expectation that they are buried in natively folded proteins. We applied QCDPred to the yeast proteome, enabling us to analyse more widely the potential effects of degrons. As an example, we show a correlation between cellular abundance and degron potential in disordered regions of proteins. Together with recent results on membrane proteins, our work suggest that the recognition of exposed hydrophobic residues is a key and generic mechanism for proteome homeostasis. QCDPred is freely available as open source code and via a web interface. 相似文献
615.
616.
Santiago Saura 《Journal of Biogeography》2021,48(1):11-22
The habitat amount hypothesis (HAH) predicts that species richness in a habitat site increases with the amount of habitat in the ‘local landscape’ defined by an appropriate distance around the site, with no distinct effects of the size of the habitat patch in which the site is located. It has been stated that a consequence of the HAH, if supported, would be that it is unnecessary to consider habitat configuration to predict or manage biodiversity patterns, and that conservation strategies should focus on habitat amount regardless of fragmentation. Here, I assume that the HAH holds and apply the HAH predictions to all habitat sites over entire landscapes that have the same amount of habitat but differ in habitat configuration. By doing so, I show that the HAH actually implies clearly negative effects of habitat fragmentation, and of other spatial configuration changes, on species richness in all or many of the habitat sites in the landscape, and that these habitat configuration effects are distinct from those of habitat amount in the landscape. I further show that, contrary to current interpretations, the HAH is compatible with a steeper slope of the species–area relationship for fragmented than for continuous habitat, and with higher species richness for a single large patch than for several small patches with the same total area (SLOSS). This suggests the need to revise the ways in which the HAH has been interpreted and can be actually tested. The misinterpretation of the HAH has arisen from confounding and overlooking the differences in the spatial scales involved: the individual habitat site at which the HAH gives predictions, the local landscape around an individual site and the landscapes or regions (with multiple habitat sites and different local landscapes) that need to be analysed and managed. The HAH has been erroneously viewed as negating or diminishing the relevance of fragmentation effects, while it actually supports the importance of habitat configuration for biodiversity. I conclude that, even in the cases where the HAH holds, habitat fragmentation and configuration are important for understanding and managing species distributions in the landscape. 相似文献
617.
Most analyses of dental enamel hypoplasia compare frequencies of disturbed tooth types, which do not account for variability in the area of affected enamel. An alternate methodology, hypoplastic area, is presented here that accounts for this variability by combining acute and continuous enamel hypoplasia into an interval-level variable. The method compares samples based on individuals, by multiple tooth type variables, or by a single value rather than by tooth types. Use of the hypoplastic area method is illustrated by analyzing human skeletal dentitions in three archaeological samples: Meroitic Nubians from Semna South, Sudan; Anasazi from Navajo Reservoir, New Mexico; and Mogollon from Grasshopper Pueblo, Arizona. Both univariate and multivariate statistical tests are employed to assess variation in defects between individuals and samples. By incorporating measurements of continuous defects, the hypoplastic area method provides information beyond that of frequency data in comparing levels of stress. Flexibility of the method is also discussed. © 1995 Wiley-Liss, Inc. 相似文献
618.
Sjoerd R. Murris John T. Arsenault Rajani Raman Rufin Vogels Wim Vanduffel 《Neuron》2021,109(8):1381-1395.e7
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619.
Norbert Kučerka Stephanie Tristram-Nagle John F. Nagle 《The Journal of membrane biology》2006,208(3):193-202
Quantitative structures are obtained at 30°C for the fully hydrated fluid phases of palmitoyloleoylphosphatidylcholine (POPC), with a double bond on the sn-2 hydrocarbon chain, and for dierucoylphosphatidylcholine (di22:1PC), with a double bond on each hydrocarbon chain. The form factors F(q z ) for both lipids are obtained using a combination of three methods. (1) Volumetric measurements provide F(0). (2) X-ray scattering from extruded unilamellar vesicles provides ΙF(q z )Ι for low q z . (3) Diffuse X-ray scattering from oriented stacks of bilayers provides ΙF(q z )Ι for high q z . Also, data using method (2) are added to our recent data for dioleoylphosphatidylcholine (DOPC) using methods (1) and (3); the new DOPC data agree very well with the recent data and with (4) our older data obtained using a liquid crystallographic X-ray method. We used hybrid electron density models to obtain structural results from these form factors. The result for area per lipid (A) for DOPC 72.4 ± 0.5 Å2 agrees well with our earlier publications, and we find A = 69.3 ± 0.5 Å2 for di22:1PC and A = 68.3 ± 1.5 Å2 for POPC. We obtain the values for five different average thicknesses: hydrophobic, steric, head-head, phosphate-phosphate and Luzzati. Comparison of the results for these three lipids and for our recent dimyristoylphosphatidylcholine (DMPC) determination provides quantitative measures of the effect of unsaturation on bilayer structure. Our results suggest that lipids with one monounsaturated chain have quantitative bilayer structures closer to lipids with two monounsaturated chains than to lipids with two completely saturated chains. 相似文献
620.
David W. Schindler 《Ecosystems》1998,1(4):323-334
The results of bottle and mesocosm experiments were compared with those obtained in whole-ecosystem experiments at the Experimental
Lakes Area. Unless they can be cleverly designed to mimic major ecosystem processes and community compositions, smaller-scale
experiments often give highly replicable, but spurious, answers. Problems with appropriate scaling are difficult to deduce
without direct comparisons with whole-ecosystem experiments. Reasons are many, but include inappropriate spatial scales to
include whole communities, in particular predators and nocturnally active animals; temporal scales that are too short to assess
accurately the response of slow-responding organisms and biogeochemical processes; and elimination of key littoral–pelagic
and catchment–lake interactions. Identical studies of limnological processes in lakes of a large range of sizes reveals that
scaling correction is also necessary when extrapolating from small lakes to large ones. Accurate management decisions cannot
be made with confidence unless ecosystem scales are studied.
Received 26 March 1998; accepted 14 May 1998. 相似文献