Ion and ligand interactions of hyaluronic acid

透明质酸的离子和配体相互作用

• 批准号: 2005189
• 负责人: Omar Saleh
• 金额: $ 47.75万
• 依托单位: University of California-Santa Barbara
• 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: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2005189&HistoricalAwards=false
• 关键词: Ion; ligand; interactions; hyaluronic; acid

NONTECHNICAL ABSTRACTHyaluronic acid is a biological molecule with a range of functions. It is an integral component of cartilage, where it plays a biomechanical role in promoting healthy joint function. Further, since it can be obtained in large quantities, and can be chemically modified, it has become widely studied for biomedical and biomaterial applications. These biological and technological roles rely on hyaluronic acid’s physical features: it is a long, linear polymer that is highly charged and water soluble, and it has a variety of interactions, both with salt ions and with biomolecular binding partners, that modify its structure and behavior. However, compared to other biopolymers (such as DNA or cytoskeletal components), the basic physical behavior of hyaluronic acid has not been extensively studied.The main goal of the present project is to perform precision measurements of the physical behavior of hyaluronic acid, and its modification by ions and other molecules. The researchers will carry out such experiments using modern biophysical approaches, and interpret them using advanced theoretical methods. Experiments will be focused on two areas: first, researchers will quantify electrostatic effects of salt on hyaluronic acid behavior, and particularly pursue understanding of physiologically-relevant mixed-salt conditions on molecular shape. Second, researchers will investigate the hypothesis that dramatic shape-changes can be induced in hyaluronic acid upon binding to specific biomolecular partners. Overall, the scientific work in this project will result in direct, quantitative estimates of the role of salt and biomolecular-binding in affecting hyaluronic acid behavior; in turn, this will lead to better understanding of the molecule’s various biological roles, and will permit rational engineering of hyaluronic acid in biomaterials environments. These scientific impacts are complemented by a range of other benefits, notably including a major effort to broaden graduate-student training through an exchange program with a German university, focused on teaching modern computational methods to bioengineers and biophysicists. Other benefits will accrue from collaboration with a national lab, and enhancing STEM human resources through undergraduate student training. TECHNICAL ABSTRACTHyaluronic acid, HA, is a long, linear, negatively-charged polysaccharide with moderate conformational flexibility. It plays broad biological roles, particularly in defining the mechanical and viscoelastic properties of extracellular spaces. HA’s properties have also led to broad investigation of its use as a synthetic biomaterial, e.g. forming injectables or cell/tissue growth substrates. The polymeric properties of HA underlie these biological and biotechnological roles, but are understudied. The overarching goal of this proposal is to fill that gap in knowledge by performing high-resolution physical measurements, supported by advanced theoretical interpretation methods, of ion- and ligand-induced HA conformational behaviors. The researchers will apply a unique single-molecule mechanics instrument to carry out precision measurements of HA’s solution-mediated conformational and mechanical properties. Specific goals include 1) exploiting machine-learning methods to improve instrument capabilities in screening biomolecular elasticity; 2) validating and exploring a recent finding that HA conformation in mixed-ionic conditions is dominated by an ‘ion jacket’ that screens the effect of bulk salt concentration; and 3) studying the effects of specific biological ligands on HA conformation, with a focus on ligands posited to induce a helix/coil transition in the chain, and those that cause global chain swelling. Experimental results will be interpreted with reference to analytical theories of solution electrostatics and polymer bottle-brush behavior, as well as coarse-grained molecular dynamics simulations.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.

非技术摘要透明质酸是一种具有多种功能的生物分子。它是软骨的一个组成部分，在促进健康的关节功能方面发挥着生物力学作用。此外，由于它可以大量获得，并且可以进行化学修饰，因此它已被广泛研究用于生物医学和生物材料应用。这些生物和技术作用依赖于透明质酸的物理特征：它是一种长的线性聚合物，具有高电荷和水溶性，并且与盐离子和生物分子结合伙伴具有多种相互作用，从而改变其结构和行为。然而，与其他生物聚合物（例如DNA或细胞骨架成分）相比，透明质酸的基本物理行为尚未得到广泛研究。本项目的主要目标是对透明质酸的物理行为及其通过离子和其他分子的修饰进行精确测量。研究人员将利用现代生物物理方法进行此类实验，并利用先进的理论方法对其进行解释。实验将集中在两个领域：首先，研究人员将量化盐对透明质酸行为的静电效应，特别是了解生理相关的混合盐条件对分子形状的影响。其次，研究人员将研究以下假设：透明质酸在与特定的生物分子伴侣结合后会引起剧烈的形状变化。总体而言，该项目的科学工作将对盐和生物分子结合在影响透明质酸行为中的作用进行直接、定量的估计；反过来，这将有助于更好地理解该分子的各种生物学作用，并允许在生物材料环境中对透明质酸进行合理的工程设计。这些科学影响得到了一系列其他好处的补充，特别是通过与德国大学的交换项目扩大研究生培训的重大努力，重点是向生物工程师和生物物理学家教授现代计算方法。与国家实验室的合作以及通过本科生培训增强 STEM 人力资源将带来其他好处。 技术摘要透明质酸 (HA) 是一种长的、线性的、带负电荷的多糖，具有中等的构象灵活性。它发挥着广泛的生物学作用，特别是在定义细胞外空间的机械和粘弹性特性方面。 HA 的特性也引发了对其作为合成生物材料用途的广泛研究，例如形成注射剂或细胞/组织生长基质。 HA 的聚合特性是这些生物学和生物技术作用的基础，但尚未得到充分研究。该提案的总体目标是在先进的理论解释方法的支持下，通过对离子和配体诱导的 HA 构象行为进行高分辨率物理测量来填补知识空白。研究人员将应用独特的单分子力学仪器对HA的溶液介导的构象和机械特性进行精确测量。具体目标包括1）利用机器学习方法提高仪器筛选生物分子弹性的能力； 2) 验证和探索最近的发现，即混合离子条件下的 HA 构象由“离子夹套”主导，该“离子夹套”可屏蔽大量盐浓度的影响； 3) 研究特定生物配体对 HA 构象的影响，重点关注诱导链中螺旋/卷曲转变的配体，以及引起整体链膨胀的配体。实验结果将参考溶液静电学和聚合物瓶刷行为的分析理论以及粗粒度分子动力学模拟进行解释。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值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

Flexible, charged biopolymers in monovalent and mixed-valence salt: Regimes of anomalous electrostatic stiffening and of salt insensitivity

单价和混合价盐中的柔性带电生物聚合物：异常静电硬化和盐不敏感性的机制

• DOI: 10.1103/physreve.104.014504
• 发表时间: 2021
• 期刊: Physical Review E
• 影响因子: 2.4
• 作者: Innes-Gold, Sarah N.;Jacobson, David R.;Pincus, Philip A.;Stevens, Mark J.;Saleh, Omar A.
• 通讯作者: Saleh, Omar A.

Single-Molecule Stretching Shows Glycosylation Sets Tension in the Hyaluronan-Aggrecan Bottlebrush

• DOI: 10.1016/j.bpj.2020.08.016
• 发表时间: 2020-10-06
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Innes-Gold, Sarah N.;Berezney, John P.;Saleh, Omar A.
• 通讯作者: Saleh, Omar A.