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排序方式: 共有331条查询结果,搜索用时 15 毫秒
41.
Christoph Malisi Marcel Schumann Nora C. Toussaint Jorge Kageyama Oliver Kohlbacher Birte H?cker 《PloS one》2012,7(12)
Engineering specific interactions between proteins and small molecules is extremely useful for biological studies, as these interactions are essential for molecular recognition. Furthermore, many biotechnological applications are made possible by such an engineering approach, ranging from biosensors to the design of custom enzyme catalysts. Here, we present a novel method for the computational design of protein-small ligand binding named PocketOptimizer. The program can be used to modify protein binding pocket residues to improve or establish binding of a small molecule. It is a modular pipeline based on a number of customizable molecular modeling tools to predict mutations that alter the affinity of a target protein to its ligand. At its heart it uses a receptor-ligand scoring function to estimate the binding free energy between protein and ligand. We compiled a benchmark set that we used to systematically assess the performance of our method. It consists of proteins for which mutational variants with different binding affinities for their ligands and experimentally determined structures exist. Within this test set PocketOptimizer correctly predicts the mutant with the higher affinity in about 69% of the cases. A detailed analysis of the results reveals that the strengths of PocketOptimizer lie in the correct introduction of stabilizing hydrogen bonds to the ligand, as well as in the improved geometric complemetarity between ligand and binding pocket. Apart from the novel method for binding pocket design we also introduce a much needed benchmark data set for the comparison of affinities of mutant binding pockets, and that we use to asses programs for in silico design of ligand binding. 相似文献
42.
EF Toussaint FL Condamine GJ Kergoat C Capdevielle-Dulac J Barbut JF Silvain BP Le Ru 《PloS one》2012,7(7):e41377
Between the late Oligocene and the early Miocene, climatic changes have shattered the faunal and floral communities and drove the apparition of new ecological niches. Grassland biomes began to supplant forestlands, thus favouring a large-scale ecosystem turnover. The independent adaptive radiations of several mammal lineages through the evolution of key innovations are classic examples of these changes. However, little is known concerning the evolutionary history of other herbivorous groups in relation with this modified environment. It is especially the case in phytophagous insect communities, which have been rarely studied in this context despite their ecological importance. Here, we investigate the phylogenetic and evolutionary patterns of grass-specialist moths from the species-rich tribe Apameini (Lepidoptera, Noctuidae). The molecular dating analyses carried out over the corresponding phylogenetic framework reveal an origin around 29 million years ago for the Apameini. Ancestral state reconstructions indicate (i) a potential Palaearctic origin of the tribe Apameini associated with a major dispersal event in Afrotropics for the subtribe Sesamiina; (ii) a recent colonization from Palaearctic of the New World and Oriental regions by several independent lineages; and (iii) an ancestral association of the tribe Apameini over grasses (Poaceae). Diversification analyses indicate that diversification rates have not remained constant during the evolution of the group, as underlined by a significant shift in diversification rates during the early Miocene. Interestingly, this age estimate is congruent with the development of grasslands at this time. Rather than clade ages, variations in diversification rates among genera better explain the current differences in species diversity. Our results underpin a potential adaptive radiation of these phytophagous moths with the family Poaceae in relation with the major environmental shifts that have occurred in the Miocene. 相似文献
43.
Proteins involved in membrane remodeling play an essential role in a plethora of cell functions including endocytosis and intracellular transport. Defects in several of them lead to human diseases. Myotubularins, amphiphysins, and dynamins are all proteins implicated in membrane trafficking and/or remodeling. Mutations in myotubularin, amphiphysin 2 (BIN1), and dynamin 2 lead to different forms of centronuclear myopathy, while mutations in myotubularin-related proteins cause Charcot-Marie-Tooth neuropathies. In addition to centronuclear myopathy, dynamin 2 is also mutated in a dominant form of Charcot-Marie-Tooth neuropathy. While several proteins from these different families are implicated in similar diseases, mutations in close homologues or in the same protein in the case of dynamin 2 lead to diseases affecting different tissues. This suggests (1) a common molecular pathway underlying these different neuromuscular diseases, and (2) tissue-specific regulation of these proteins. This review discusses the pathophysiology of the related neuromuscular diseases on the basis of animal models developed for proteins of the myotubularin, amphiphysin, and dynamin families. A better understanding of the common mechanisms between these neuromuscular disorders will lead to more specific health care and therapeutic approaches. 相似文献
44.
Berthelot G Thibault V Tafflet M Escolano S El Helou N Jouven X Hermine O Toussaint JF 《PloS one》2008,3(2):e1552
World records (WR) in sports illustrate the ultimate expression of human integrated muscle biology, through speed or strength performances. Analysis and prediction of man's physiological boundaries in sports and impact of external (historical or environmental) conditions on WR occurrence are subject to scientific controversy. Based on the analysis of 3263 WR established for all quantifiable official contests since the first Olympic Games, we show here that WR progression rate follows a piecewise exponential decaying pattern with very high accuracy (mean adjusted r(2) values = 0.91+/-0.08 (s.d.)). Starting at 75% of their estimated asymptotic values in 1896, WR have now reached 99%, and, present conditions prevailing, half of all WR will not be improved by more than 0,05% in 2027. Our model, which may be used to compare future athletic performances or assess the impact of international antidoping policies, forecasts that human species' physiological frontiers will be reached in one generation. This will have an impact on the future conditions of athlete training and on the organization of competitions. It may also alter the Olympic motto and spirit. 相似文献
45.
Prokaryotic mobile elements have traditionally been classified as bacteriophages, plasmids, and transposons. We propose here a global classification of these and other bacterial and archaeal mobile elements based on their modular structure. This would allow for setting up interconnected databases where mobile elements could be stored as combinations of functional modules. Such a database would be very helpful. It would, for instance, allow for analyzing the phylogeny of individual blocks within an element, to understand how modules get associated and properly express the functions they carry in various bacterial hosts. Modules of practical importance, as for instance those that encode toxins or other virulence factors, could be identified and compared, and probes devised to test bacterial populations for the presence of such modules. 相似文献
46.
Stimulation of deletions in the Escherichia coli chromosome by partially induced Mucts62 prophages. 总被引:7,自引:7,他引:0
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Deletion of bacterial DNA fragments is stimulated in induced Mucts62 lysogens. The host genes located proximally to the prophage are more frequently lost than those which are unlinked to the Mu genome. Genes located on either side of a Mu genome are deleted in the same manner. Like the other Mu-induced rearrangements, this process is recA independent and requires the participation of Mu DNA, as indicated by the fact that a phage genome always replaces the deleted genes. Data are presented which strongly suggest that both ends of the Mu genome are involved in deletion formation. 相似文献
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50.
Yasser Iturria-Medina Roberto C. Sotero Paule J. Toussaint Alan C. Evans and the Alzheimer's Disease Neuroimaging Initiative 《PLoS computational biology》2014,10(11)
Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer''s disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain''s clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer''s disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders. 相似文献