Collaborative Research: Conformational Equilibria of Biologically Important Saccharides and Related Biomolecules

合作研究：具有重要生物学意义的糖类和相关生物分子的构象平衡

• 批准号: 2002628
• 负责人: Robert Woods
• 金额: $ 7.2万
• 依托单位: University of Georgia Research Foundation Inc
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2002628&HistoricalAwards=false
• 关键词: Collaborative; Research; Conformational; Equilibria; Biologically

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Anthony Serianni from the University of Notre Dame and Dr. Robert Woods from the University of Georgia to investigate the three-dimensional properties of sugar molecules, or saccharides, in solution. Saccharides embedded in cell surfaces play critical roles in biology. In humans, they are attached to soluble and membrane associated proteins and lipids, and their biological roles include cell-to-cell and immune recognition. While it is well known that the structural properties of saccharides correlate with their biological functions, it remains difficult to assign these structural details in solution by experimental methods. This difficulty has led to a heavy reliance on theoretical methods to assign structures even though these methods have been difficult to validate experimentally. This project aims to solve this problem by developing and applying a new experimental technique to determine populations of flexible domains in saccharides in solution, including the linkages connecting them together in polymers and linkages that attach them to other biomolecules. The experiment-derived information obtained can be compared to what is obtained from theory to test and/or validate the latter. Senior researchers, graduate students and undergraduates with interests and expertise in experimental and computational science collaborate to achieve the objectives of the project. This work provides valuable new tools to determine molecular structure that can be generally applied to any biomolecule in solution, including proteins and nucleic acids.This research project uses stable isotopically labeled oligosaccharides and glycopeptides, nuclear magnetic resonance (NMR) spin-couplings, density functional theory calculations, circular statistics and X-ray crystallography to determine conformational populations of the flexible domains of oligosaccharides in solution. This experimental approach is possible because saccharides contain multiple NMR spin-couplings that report on the same conformational domain, allowing quantitative treatments that yield continuous single- and multi-state populational models. Once a given domain is parameterized (e.g., O- or N-glycosidic linkage), its conformational properties can be investigated in different structural contexts to determine the degree to which it adapts conformationally to environmental cues. Experimental models are compared to those obtained from molecular dynamics simulations to validate the latter. This work leads to new experiment-based conformational classifications of O-glycosidic linkages in oligosaccharides, and to a deeper understanding of the multiple factors that influence oligosaccharide conformation in solution.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该奖项将资助圣母大学的Anthony Serianni博士和佐治亚大学的Robert Wood博士研究糖分子或糖在溶液中的三维性质。镶嵌在细胞表面的糖类在生物学中起着至关重要的作用。在人类中，它们附着在可溶性和膜相关的蛋白质和脂类上，它们的生物学作用包括细胞间识别和免疫识别。虽然众所周知，糖的结构性质与它们的生物学功能有关，但仍然很难用实验方法确定这些结构细节在溶液中的位置。这一困难导致了对理论方法的严重依赖来指定结构，尽管这些方法很难通过实验进行验证。该项目旨在通过开发和应用一种新的实验技术来确定溶液中糖的柔性结构域群来解决这一问题，包括在聚合物中将它们连接在一起的连接以及将它们连接到其他生物分子上的连接。可以将从实验获得的信息与从理论获得的信息进行比较，以测试和/或验证后者。对实验和计算科学有兴趣和专业知识的资深研究人员、研究生和本科生合作实现该项目的目标。这项工作提供了有价值的新工具来确定一般应用于溶液中任何生物分子的分子结构，包括蛋白质和核酸。本研究项目使用稳定的同位素标记的寡糖和糖肽、核磁共振自旋偶联、密度泛函理论计算、循环统计和X射线结晶学来确定溶液中低聚糖柔性结构域的构象布居。这种实验方法是可能的，因为糖包含多个在同一构象结构域上报告的核磁共振自旋偶联，从而允许定量处理产生连续的单态和多态种群模型。一旦给定的结构域被参数化(例如，O-或N-糖苷键)，就可以在不同的结构背景下研究其构象性质，以确定它在构象上适应环境提示的程度。将实验模型与分子动力学模拟结果进行了比较，验证了分子动力学模拟的正确性。这项工作导致了低聚糖中O-糖苷键的新的基于实验的构象分类，并加深了对溶液中影响低聚糖构象的多种因素的理解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Computationally guided conversion of the specificity of E-selectin to mimic that of Siglec-8.

• DOI: 10.1073/pnas.2117743119
• 发表时间: 2022-10-11
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

Does Inter-Residue Hydrogen Bonding in β-(1→4)-Linked Disaccharides Influence Linkage Conformation in Aqueous Solution?

• DOI: 10.1021/acs.jpcb.3c07448
• 发表时间: 2024-02-28
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY B
• 影响因子: 3.3
• 作者: Zhang，Wenhui;Meredith，Reagan J.;Serianni，Anthony S.
• 通讯作者: Serianni，Anthony S.