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1.
《Journal of molecular biology》2021,433(22):167254
Tau is an intrinsically disordered protein implicated in many neurodegenerative diseases. The repeat domain fragment of tau, tau-K18, is known to undergo a disorder to order transition in the presence of lipid micelles and vesicles, in which helices form in each of the repeat domains. Here, the mechanism of helical structure formation, induced by a phospholipid mimetic, sodium dodecyl sulfate (SDS) at sub-micellar concentrations, has been studied using multiple biophysical probes. A study of the conformational dynamics of the disordered state, using photoinduced electron transfer coupled to fluorescence correlation spectroscopy (PET-FCS) has indicated the presence of an intermediate state, I, in equilibrium with the unfolded state, U. The cooperative binding of the ligand (L), SDS, to I has been shown to induce the formation of a compact, helical intermediate (IL5) within the dead time (∼37 µs) of a continuous flow mixer. Quantitative analysis of the PET-FCS data and the ensemble microsecond kinetic data, suggests that the mechanism of induction of helical structure can be described by a U ↔ I ↔ IL5 ↔ FL5 mechanism, in which the final helical state, FL5, forms from IL5 with a time constant of 50–200 µs. Finally, it has been shown that the helical conformation is an aggregation-competent state that can directly form amyloid fibrils. 相似文献
2.
《Bioorganic & medicinal chemistry》2016,24(8):1778-1785
As part of a selection strategy for artificial nucleic acids (XNA) (to be considered as potential new information systems in vivo), we have carried out a modelling study on cyclohexanyl nucleic acids (CNA) duplexes and hairpins. CNA may form a duplex as well as hairpin structures, having the carbocyclic nucleosides in the 4C1 conformation (with equatorial basis). The geometry of ds CNA is close to that of a HNA:RNA duplex. We demonstrated that CNA triphosphates function as a substrate for polymerases. Modelling experiments indicate that the monomers are probably presented to the polymerase in the 1C4 conformation. 相似文献
3.
AbstractIn the present paper, computational efficiency of the hybrid Monte Carlo (HMC) method applied to the multicanonical ensemble is studied; the HMC is an equation of motion guided Monte Carlo method. As in the standard HMC for the canonical ensemble, the multicanonical HMC calculations with high acceptance ratio show better efficiency; about 60% acceptance yields the best performance for the system examined. 相似文献
4.
5.
《Bioorganic & medicinal chemistry》2014,22(13):3316-3324
Desymmetrization of the pseudochiral (2r)-configured cyclohexane-1,2,3-triamines 8 with dimethyl oxalate led to racemic aminoquinoxaline-2,3-diones 9. Selective introduction of the κ pharmacophoric structural elements pyrrolidine and 3,4-dichlorophenylacetamide with a two-carbon distance afforded conformationally restricted κ agonists 13–15 based on the quinoxaline ring system. In competitive radioligand receptor binding studies the benzylamine 13b, the secondary amine 14b, and the carbamate 15 displayed high κ receptor affinity. The Ki value of the lead compound derived methoxycarbonyl derivative 15 is 9.7 nM. However, the κ affinity of 15 is exceeded by 13b and 14b with a basic functional group instead of the methoxycarbonyl group in 1-position of the quinoxaline system. The chlorine atoms of the dichlorophenylacetyl residue are essential, since the corresponding phenylacetyl analogs show considerably reduced κ affinity. The potent κ ligands 13b, 14b and 15 are selective over the related μ- and δ-opioid receptors, σ1, σ2 and NMDA receptors. In the [35S]GTPγS-binding assay 13b behaved as partial agonist with lower activity than U-69,593. 相似文献
6.
7.
The temperature dependence of the kinetics of the binding of ATP to myosin subfragment-1 was studied by an ATP chase technique in a rapid-flow-quench apparatus: (formula; see text) A temperature range of 30 degrees C to -15 degrees C was obtained with ethylene glycol as antifreeze. The Arrhenius plot of k2 is discontinuous with a jump at 12 degrees C. Above the jump delta H+ = 9.5 kcal/mol, below delta H+ = 28.5 kcal/mol. Few such Arrhenius plots are recorded in the literature but they are predicted from theory. Thus, we explain our results as a phase change of the subfragment 1-ATP system at 12 degrees C. This is in agreement with certain structural studies. 相似文献
8.
To obtain a satisfactory agreement between computed transition temperatures and those determined experimentally, we introduce explicitly water molecules which hydrate the polar headgroup of dipalmitoylphosphatidylethanolamine molecules. The calculated free energy curves as a function of the intermolecular interchain distance and the degree of hydration of the polar groups permit the determination of the transition of the phospholipid system from the gel to the liquid crystalline phase. The detailed structure of the hydration shell is defined using the supermolecular approach. 相似文献
9.
Graham Oppy 《Biology & philosophy》1996,11(4):519-534
There seems to be a widespread conviction — evidenced, for example, in the work of Mackie, Dawkins and Sober — that it is Darwinian rather than Humean considerations which deal the fatal logical blow to arguments for intelligent design. I argue that this conviction cannot be well-founded. If there are current logically decisive objections to design arguments, they must be Humean — for Darwinian considerations count not at all against design arguments based upon apparent cosmological fine-tuning. I argue, further, that there are good Humean reasons for atheists and agnostics to resist the suggestion that apparent design — apparent biological design and/or apparent cosmological fine-tuning — establishes (or even strongly supports) the hypothesis of intelligent design. 相似文献
10.
An empirical projection method is described to predict the magnitudes and signs of two-bond 13C-13C spin-coupling constants (2JCC) in aldopyranosyl rings. The method has been applied primarily to the interpretation of 2JCCC values, although the behavior of 2JCOC has also been examined in light of the new approach, producing results which may prove useful in the conformational analysis of O-glycosidic linkages in oligosaccharides. High-level ab initio calculations of 2JCC values in model compounds were found to be in agreement with the predictions. 相似文献