Application of hydrogen bond enhanced halogen bond for biomolecular engineering

氢键增强卤键在生物分子工程中的应用

• 批准号: 1905328
• 负责人: Pui Ho
• 金额: $ 56.99万
• 依托单位: Colorado State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1905328&HistoricalAwards=false
• 关键词: Application; hydrogen; bond; enhanced; halogen

Halogens (fluorine, chlorine, bromine, and iodine) are elements found in 25% of drugs currently used to treat human disease. The role of halogens in providing drugs with their specificity against clinical targets is now recognized as coming from a chemical interaction called the halogen bond. The halogen bond is similar to the better-recognized hydrogen bond, which is responsible for holding the structures of DNA and proteins together. With this award, the Chemistry of Life Processes program of the Chemistry Division is funding Professor Laurie Stargell and Professor Anthony Rappe to determine how hydrogen bonds enhance the strength of halogen bonds, allowing this now stronger interaction to be engineered to design new proteins. The enhanced halogen bonds will be used to create proteins that interact with other proteins, leading to a new computer method to design drugs to treat human disease. In addition, the enhanced halogen bonds stabilize proteins that are otherwise not entirely stable, which has been associated with neurodegenerative diseases such as Alzheimer's disease. This project will provide training in structural and computational chemistry for graduate and undergraduate students, including those from underrepresented groups. Finally, an outreach project will help middle school and high school students learn how scientists use 'X-ray vision' to see the atoms in DNA and proteins.The hydrogen bond (HB) is a well-characterized and prevalent interaction in biology. The halogen bond (XB) is increasingly being recognized as important in chemistry and biology, particularly in biomolecular engineering and in the design of inhibitors against biomolecular targets. Very recently, it was shown that an HB donor can significantly increase the XB potential of an adjacent halogen substituent through a variation called an HB-enhanced XB (or HBeXB, for short). This project will test the hypothesis that HBeXBs are strongly stabilizing interactions that can be exploited in biomolecular engineering and inhibitor design. In order to realize the potential of the HBeXB as a design tool, its structure-energy relationships must be characterized and incorporated into a molecular simulation algorithm. The objectives of this project are to determine the prevalence of HBeXBs in the chemical and protein structural databases; incorporate HBeXBs into an empirical force field for halogen bonds to accurately model this synergistic interaction; and engineer HBeXBs into coiled coil peptides and partially stable proteins to validate this new force field and as a proof of concept for bimolecular engineering.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.

卤素（氟，氯，溴和碘）是目前用来治疗人类疾病的25％的元素。现在，卤素在为临床靶标提供特异性的药物方面的作用被认为来自一种称为卤素键的化学相互作用。卤素键类似于获得更好认可的氢键，该氢键负责将DNA和蛋白质的结构固定在一起。有了这个奖项，化学过程的化学过程计划是为劳里·斯塔格尔（Laurie Stargell）教授和安东尼·拉佩（Anthony Rappe）教授提供资金，以确定氢键如何增强卤素键的强度，从而使这种现在更强的相互作用可以设计用于设计新蛋白质。增强的卤素键将用于创建与其他蛋白质相互作用的蛋白质，从而导致一种新的计算机方法来设计治疗人类疾病的药物。此外，增强的卤素键可以稳定蛋白质，这些蛋白质本来并不完全稳定，这与神经退行性疾病有关，例如阿尔茨海默氏病。该项目将为研究生和本科生（包括来自代表性不足的小组的研究生和本科生）提供结构和计算化学的培训。最后，一个外展项目将帮助中学和高中生学习科学家如何使用“ X射线视觉”来查看DNA和蛋白质中的原子。氢键（HB）是一种在生物学中的表征良好且普遍的相互作用。卤素键（XB）越来越多地被认为在化学和生物学中很重要，尤其是在生物分子工程以及针对生物分子靶标的抑制剂的设计中。最近，发现HB供体可以通过称为HB增强XB（或HBEXB，简称）的变体显着提高相邻卤素取代基的XB电位。该项目将检验以下假设：HBEXBS强烈稳定可以在生物分子工程和抑制剂设计中利用的相互作用。为了实现HBEXB作为设计工具的潜力，必须将其结构 - 能源关系表征并纳入分子模拟算法中。该项目的目标是确定化学和蛋白质结构数据库中HBEXB的普遍性；将HBEXBS纳入卤素键的经验力场中，以准确对这种协同相互作用进行建模。以及HBEXBS的工程师进入盘绕的线圈肽和部分稳定的蛋白质，以验证该新的力领域，并作为双分子工程的概念证明。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的审查标准来通过评估来获得支持的。

项目成果

Structural adaptation of vertebrate endonuclease G for 5-hydroxymethylcytosine recognition and function

• DOI: 10.1093/nar/gkaa117
• 发表时间: 2020-02
• 期刊: Nucleic Acids Research
• 影响因子: 14.9
• 作者: Crystal M Vander Zanden-Crystal-M-Vander Zanden-2127635681;R. S. Czarny;Ethan N Ho;A. Robertson;P. S. Ho