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51.
52.
Multidimensional heteronuclear NMR studies have been applied to the
resonance assignment and conformational analysis of 13C-enriched
Neu5Acalpha2-3Galbeta1-4Glc. It is demonstrated that three-dimensional
ROESY-HSQC experiments provide through-space distance restraints which
cannot be observed with conventional homonuclear 1H techniques due to
resonance overlap. In particular, connectivities demonstrating the
existence of the "anti" conformation about the Galbeta1-4Glc glycosidic
linkage are unambiguously observed. It is shown that 13C isotopic
enrichment of the trisaccharide at a level >95% enables straightforward
measurement of trans-glycosidic 1H-13C and 13C-13C coupling constants and a
Karplus-type relation is derived for the latter. In total 15 conformational
restraints were obtained for the trisaccharide in aqueous solution, all of
which were in excellent agreement with theoretical parameters computed from
a 5 ns molecular dynamics simulation of the glycan.
相似文献
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54.
Stuart A. MacGowan Michael I. Barton Mikhail Kutuzov Omer Dushek P. Anton van der Merwe Geoffrey J. Barton 《PLoS computational biology》2022,18(3)
SARS-CoV-2 Spike (Spike) binds to human angiotensin-converting enzyme 2 (ACE2) and the strength of this interaction could influence parameters relating to virulence. To explore whether population variants in ACE2 influence Spike binding and hence infection, we selected 10 ACE2 variants based on affinity predictions and prevalence in gnomAD and measured their affinities and kinetics for Spike receptor binding domain through surface plasmon resonance (SPR) at 37°C. We discovered variants that reduce and enhance binding, including three ACE2 variants that strongly inhibited (p.Glu37Lys, ΔΔG = –1.33 ± 0.15 kcal mol-1 and p.Gly352Val, predicted ΔΔG = –1.17 kcal mol-1) or abolished (p.Asp355Asn) binding. We also identified two variants with distinct population distributions that enhanced affinity for Spike. ACE2 p.Ser19Pro (ΔΔG = 0.59 ± 0.08 kcal mol-1) is predominant in the gnomAD African cohort (AF = 0.003) whilst p.Lys26Arg (ΔΔG = 0.26 ± 0.09 kcal mol-1) is predominant in the Ashkenazi Jewish (AF = 0.01) and European non-Finnish (AF = 0.006) cohorts. We compared ACE2 variant affinities to published SARS-CoV-2 pseudotype infectivity data and confirmed that ACE2 variants with reduced affinity for Spike can protect cells from infection. The effect of variants with enhanced Spike affinity remains unclear, but we propose a mechanism whereby these alleles could cause greater viral spreading across tissues and cell types, as is consistent with emerging understanding regarding the interplay between receptor affinity and cell-surface abundance. Finally, we compared mCSM-PPI2 ΔΔG predictions against our SPR data to assess the utility of predictions in this system. We found that predictions of decreased binding were well-correlated with experiment and could be improved by calibration, but disappointingly, predictions of highly enhanced binding were unreliable. Recalibrated predictions for all possible ACE2 missense variants at the Spike interface were calculated and used to estimate the overall burden of ACE2 variants on Covid-19. 相似文献
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56.
Background
Statistical methods for identifying positively selected sites in protein coding regions are one of the most commonly used tools in evolutionary bioinformatics. However, they have been limited by not taking the physiochemical properties of amino acids into account. 相似文献57.
58.
Wahbi K. El-Bouri Andrew MacGowan Tams I. Jzsa Matthew J. Gounis Stephen J. Payne 《PLoS computational biology》2021,17(3)
Many ischaemic stroke patients who have a mechanical removal of their clot (thrombectomy) do not get reperfusion of tissue despite the thrombus being removed. One hypothesis for this ‘no-reperfusion’ phenomenon is micro-emboli fragmenting off the large clot during thrombectomy and occluding smaller blood vessels downstream of the clot location. This is impossible to observe in-vivo and so we here develop an in-silico model based on in-vitro experiments to model the effect of micro-emboli on brain tissue. Through in-vitro experiments we obtain, under a variety of clot consistencies and thrombectomy techniques, micro-emboli distributions post-thrombectomy. Blood flow through the microcirculation is modelled for statistically accurate voxels of brain microvasculature including penetrating arterioles and capillary beds. A novel micro-emboli algorithm, informed by the experimental data, is used to simulate the impact of micro-emboli successively entering the penetrating arterioles and the capillary bed. Scaled-up blood flow parameters–permeability and coupling coefficients–are calculated under various conditions. We find that capillary beds are more susceptible to occlusions than the penetrating arterioles with a 4x greater drop in permeability per volume of vessel occluded. Individual microvascular geometries determine robustness to micro-emboli. Hard clot fragmentation leads to larger micro-emboli and larger drops in blood flow for a given number of micro-emboli. Thrombectomy technique has a large impact on clot fragmentation and hence occlusions in the microvasculature. As such, in-silico modelling of mechanical thrombectomy predicts that clot specific factors, interventional technique, and microvascular geometry strongly influence reperfusion of the brain. Micro-emboli are likely contributory to the phenomenon of no-reperfusion following successful removal of a major clot. 相似文献
59.
William A. L. MacGowan 《BMJ (Clinical research ed.)》1954,1(4858):396-397
60.