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Use of atomic force microscopy (AFM) has recently led to a better understanding of the molecular mechanisms of the unfolding process by mechanical forces; however, the rational design of novel proteins with specific mechanical strength remains challenging. We have approached this problem from a new perspective that generates linear physical–chemical properties (PCP) motifs from a limited AFM data set. Guided by our linear sequence analysis, we designed and analyzed four new mutants of the titin I1 domain with the goal of increasing the domain's mechanical strength. All four mutants could be cloned and expressed as soluble proteins. AFM data indicate that at least two of the mutants have increased molecular mechanical strength. This observation suggests that the PCP method is useful to graft sequences specific for high mechanical stability to weak proteins to increase their mechanical stability, and represents an additional tool in the design of novel proteins besides steered molecular dynamics calculations, coarse grained simulations, and ?‐value analysis of the transition state. Proteins 2012; © 2011 Wiley Periodicals, Inc. 相似文献
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The flexibility of different regions of HIV-1 protease was examined by using a database consisting of 73 X-ray structures that differ in terms of sequence, ligands or both. The root-mean-square differences of the backbone for the set of structures were shown to have the same variation with residue number as those obtained from molecular dynamics simulations, normal mode analyses and X-ray B-factors. This supports the idea that observed structural changes provide a measure of the inherent flexibility of the protein, although specific interactions between the protease and the ligand play a secondary role. The results suggest that the potential energy surface of the HIV-1 protease is characterized by many local minima with small energetic differences, some of which are sampled by the different X-ray structures of the HIV-1 protease complexes. Interdomain correlated motions were calculated from the structural fluctuations and the results were also in agreement with molecular dynamics simulations and normal mode analyses. Implications of the results for the drug-resistance engendered by mutations are discussed briefly. 相似文献
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Seema Sharma Haiyan Zheng Yuanpeng J. Huang Asli Ertekin Yoshitomo Hamuro Paolo Rossi Roberto Tejero Thomas B. Acton Rong Xiao Mei Jiang Li Zhao Li‐Chung Ma G. V. T. Swapna James M. Aramini Gaetano T. Montelione 《Proteins》2009,76(4):882-894
Disordered or unstructured regions of proteins, while often very important biologically, can pose significant challenges for resonance assignment and three‐dimensional structure determination of the ordered regions of proteins by NMR methods. In this article, we demonstrate the application of 1H/2H exchange mass spectrometry (DXMS) for the rapid identification of disordered segments of proteins and design of protein constructs that are more suitable for structural analysis by NMR. In this benchmark study, DXMS is applied to five NMR protein targets chosen from the Northeast Structural Genomics project. These data were then used to design optimized constructs for three partially disordered proteins. Truncated proteins obtained by deletion of disordered N‐ and C‐terminal tails were evaluated using 1H‐15N HSQC and 1H‐15N heteronuclear NOE NMR experiments to assess their structural integrity. These constructs provide significantly improved NMR spectra, with minimal structural perturbations to the ordered regions of the protein structure. As a representative example, we compare the solution structures of the full length and DXMS‐based truncated construct for a 77‐residue partially disordered DUF896 family protein YnzC from Bacillus subtilis, where deletion of the disordered residues (ca. 40% of the protein) does not affect the native structure. In addition, we demonstrate that throughput of the DXMS process can be increased by analyzing mixtures of up to four proteins without reducing the sequence coverage for each protein. Our results demonstrate that DXMS can serve as a central component of a process for optimizing protein constructs for NMR structure determination. Proteins 2009. © 2009 Wiley‐Liss, Inc. 相似文献
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We study the dependence of folding time, nucleation site, and stability of a model beta-hairpin on the location of a cross-strand hydrophobic pair, using a coarse-grained off-lattice model with the aid of Monte Carlo simulations. Our simulations have produced 6500 independent folding trajectories dynamically, forming the basis for extensive statistical analysis. Four folding pathways, zipping-out, middle-out, zipping-in, and reptation, have been closely monitored and discussed in all seven sequences studied. A hydrophobic pair placed near the beta-turn or in the middle section effectively speed up folding; a hydrophobic pair placed close to the terminal ends or next to the beta-turn encourages stability of the entire chain. 相似文献
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Thomas Mitchell‐Olds 《Molecular ecology》2013,22(13):3427-3429
Understanding genetic variation for complex traits in heterogeneous environments is a fundamental problem in biology. In this issue of Molecular Ecology, Fournier‐Level et al. ( 2013 ) analyse quantitative trait loci (QTL) influencing ecologically important phenotypes in mapping populations of Arabidopsis thaliana grown in four habitats across its native European range. They used causal modelling to quantify the selective consequences of life history and morphological traits and QTL on components of fitness. They found phenology QTL colocalizing with known flowering time genes as well as novel loci. Most QTL influenced fitness via life history and size traits, rather than QTL having direct effects on fitness. Comparison of phenotypes among environments found no evidence for genetic trade‐offs for phenology or growth traits, but genetic trade‐offs for fitness resulted because flowering time had opposite fitness effects in different environments. These changes in QTL effects and selective consequences may maintain genetic variation among populations. 相似文献
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Bukovinszky T Gols R Hemerik L Van Lenteren JC Vet LE 《The Journal of animal ecology》2007,76(5):845-853
1. Changing plant composition in a community can have profound consequences for herbivore and parasitoid population dynamics. To understand such effects, studies are needed that unravel the underlying behavioural decisions determining the responses of parasitoids to complex habitats. 2. The searching behaviour of the parasitoid Diadegma semiclausum was followed in environments with different plant species composition. In the middle of these environments, two Brassica oleracea plants infested by the host Plutella xylostella were placed. The control set-up contained B. oleracea plants only. In the more complex set-ups, B. oleracea plants were interspersed by either Sinapis alba or Hordeum vulgare. 3. Parasitoids did not find the first host-infested plant with the same speed in the different environments. Sinapis alba plants were preferentially searched by parasitoids, resulting in fewer initial host encounters, possibly creating a dynamic enemy-free space for the host on adjacent B. oleracea plants. In set-ups with H. vulgare, also, fewer initial host encounters were found, but in this case plant structure was more likely than infochemicals to interfere with the searching behaviour of parasitoids. 4. On discovering a host-infested plant, parasitoids located the second host-infested plant with equal speed, demonstrating the effect of experience on time allocation. Further encounters with host-infested plants that had already been visited decreased residence times and increased the tendency to leave the environment. 5. Due to the intensive search of S. alba plants, hosts were encountered at lower rates here than in the other set-ups. However, because parasitoids left the set-up with S. alba last, the same number of hosts were encountered as in the other treatments. 6. Plant composition of a community influences the distribution of parasitoid attacks via its effects on arrival and leaving tendencies. Foraging experiences can reduce or increase the importance of enemy-free space for hosts on less attractive plants. 相似文献