Application of hydrogen bond enhanced halogen bond for biomolecular engineering

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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.