Application of hydrogen bond enhanced halogen bond for biomolecular engineering

卤素(氟、氯、溴和碘)是目前用于治疗人类疾病的药物中25%存在的元素。卤素在提供针对临床靶点的特异性药物方面的作用现在被认为来自一种称为卤键的化学作用。卤键类似于更广为人知的氢键，氢键负责将DNA和蛋白质的结构保持在一起。通过这一奖项，化学系的生命过程化学项目将资助Laurie Stargell教授和Anthony Rappe教授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得以设计出新的蛋白质。增强的卤素键将被用来产生与其他蛋白质相互作用的蛋白质，从而产生一种新的计算机方法来设计治疗人类疾病的药物。此外，增强的卤素键稳定了原本不完全稳定的蛋白质，这与阿尔茨海默病等神经退行性疾病有关。该项目将为研究生和本科生提供结构和计算化学方面的培训，包括那些来自代表性不足群体的学生。最后，一个推广项目将帮助初中生和高中生学习科学家如何使用“X射线视觉”来观察DNA和蛋白质中的原子。氢键(HB)是生物学中一种很好的特征和普遍存在的相互作用。卤素键(XB)在化学和生物学领域，特别是在生物分子工程和针对生物分子靶标的抑制剂的设计中，日益被认为是重要的。最近，有研究表明，Hb供体可以通过一种称为Hb增强XB(或简称HBeXB)的变体显著提高邻近卤素取代基的XB电势。该项目将测试HBeXbs具有很强稳定性的相互作用的假设，这种相互作用可用于生物分子工程和抑制剂设计。为了实现HBeXB作为设计工具的潜力，必须表征它的结构-能量关系，并将其纳入分子模拟算法。该项目的目标是确定HBeXbs在化学和蛋白质结构数据库中的普及率；将HBeXbs纳入卤素键的经验力场，以准确模拟这种协同作用；将HBeXbs设计成卷曲多肽和部分稳定的蛋白质，以验证这种新的力场，并作为双分子工程的概念验证。该奖项反映了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。

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.