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Sophie Winkler Rupert Derler Bernd Gesslbauer Elmar Krieger Andreas J. Kungl 《Biochimica et Biophysica Acta (BBA)/General Subjects》2019,1863(3):528-533
Background
Binding of chemokines to glycosaminoglycans (GAGs) is a crucial step in leukocyte recruitment to inflamed tissues.Methods
A disaccharide compositional analysis of the HS dp6 fraction in combination with MS analysis of the CCL2-depleted dp6 fraction was the basis for target GAG ligand structure suggestions. Four experimentally-derived heparan sulfate hexasaccharides, two potentially chemokine-specific and two unspecific, have been docked to CCL2. Subsequent 300?ns molecular dynamics simulations were used to improve the docked complexes.Results
Hexasaccharides with four sulfations and no acetylations are suggested for selective and high affinity chemokine binding. Using the Antithromin-III/heparin complex as positive control for docking, we were able to recover the correct complex structure only if the previously liganded ATIII structure was used as input. Since the liganded structure is not known for a CCL2-GAG complex, we investigated if molecular dynamics simulations could improve initial docking results. We found that all four GAG oligosaccharides ended up in close contact with the known binding residues after about 100?ns simulation time.Conclusions
A discrimination of specific vs. unspecific CCL2 GAG ligands is not possible by this approach. Long-time molecular dynamics simulations are, however, well suited to capture the delicate enthalpy/entropy balance of GAG binding and improve results obtained from docking.General significance
With the comparison of two methods, MS-based ligand identification and molecular modelling, we have shown the current limitations of our molecular understanding of complex ligand binding which is could be due to the numerical inaccessibility of ligand-induced protein conformational changes. 相似文献2.
Diacyl and alkylacyl glycerophosphoserines were synthesized by condensation of the respective diradylglycerophosphates with N-t-butoxycarbonyl-L-serinebenzhydryl ester in the presence of 2,4,6-triisopropylbenzenesulfonyl chloride in pyridine at room temperature. The protective groups were simultaneously removed from the resultant N-t-butoxycarbonyl-phosphatidylserinebenzhydryl esters by treatment with HCl in chloroform at 0°C. Products were obtained in 60–65% yield after purification by medium pressure liquid chromatography (MPLC). Dipalmitoyl-N-methylphosphatidylserine was synthesized by an analogous procedure. 相似文献
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锐星珊瑚(Argutastrea)是泥盆纪地层中常见的一种块状群体珊瑚,它在生物地层对比、生物地理区系划分以及古生态与古地理重建等方面都具有重要的意义。通过近年来对华南独山和奥地利格拉茨两地采集的Argutastrea群体珊瑚标本进行比较深入的对比研究,确认两地存在着一些十分相似的属种,推断彼此之间当时可能海域相通,并同属于一个老世界生物地理大区(Old World Real m)。此外,还讨论了该属与其相关的六方珊瑚(Hexagonaria)、多角珊瑚(Prismatophyllum)等属之间的异同。 相似文献
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