Extension and validation of the GLYCAM force field parameters for modeling glycosaminoglycans.
Extension and validation of the GLYCAM force field parameters for modeling glycosaminoglycans.
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DOI：
10.1139/cjc-2015-0606
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发表时间：
2016-11
影响因子：
1.1
通讯作者：
Woods RJ
中科院分区：
文献类型：
--
作者：
Singh A;Tessier MB;Pederson K;Wang X;Venot AP;Boons GJ;Prestegard JH;Woods RJ
糖胺多聚糖(GAG)是一类重要的碳水化合物，在血液凝固、组织修复、细胞迁移和黏附以及润滑中发挥关键作用。GAGS中可变的硫酸盐化模式和艾杜糖酸环的构象影响其聚合结构和相互作用的性质。本研究使用核磁共振和分子动力学模拟表征了几种类肝素GAG二糖和四糖，以帮助开发GLYCAM06力场中GAG的参数。力场添加包括O-和N-硫化的可转移硫酸盐基团、艾杜糖醛和葡萄糖糖醛酸的中性形式以及Δ4，5-不饱和尿酸(ΔUA)残基的参数和电荷。Δ尿酸残留物通常来自肝素和硫酸肝素的酶消化。对含有ΔUA的双糖的模拟表明，该残基上的硫化作用改变了1H2和2H1环构象的相对布居。模拟氨基葡萄糖残基上N-硫化取代N-乙酰化的肝素四糖会影响邻近的艾杜糖酸酯残基的环状构象。
Glycosaminoglycans (GAGs) are an important class of carbohydrates that serve critical roles in blood clotting, tissue repair, cell migration and adhesion, and lubrication. The variable sulfation pattern and iduronate ring conformations in GAGs influence their polymeric structure and nature of interaction. This study characterizes several heparin-like GAG disaccharides and tetrasaccharides using NMR and molecular dynamics simulations to assist in the development of parameters for GAGs within the GLYCAM06 force field. The force field additions include parameters and charges for a transferable sulfate group for O- and N-sulfation, neutral (COOH) forms of iduronic and glucuronic acid, and Δ4,5-unsaturated uronate (ΔUA) residues. ΔUA residues frequently arise from the enzymatic digestion of heparin and heparin sulfate. Simulations of disaccharides containing ΔUA reveal that the presence of sulfation on this residue alters the relative populations of 1H2 and 2H1 ring conformations. Simulations of heparin tetrasaccharides containing N-sulfation in place of N-acetylation on glucosamine residues influence the ring conformations of adjacent iduronate residues.