With this award, the Chemistry of Life Processes program in the Chemistry Division is supporting the research of Dr. Neal J. Zondlo at the University of Delaware in Newark, DE to study the effects of non-traditional non-covalent interactions on the structures of proteins in their normal forms and also when their amino acids have been oxidized when cells are stressed. A protein is a polymer of amino acid building blocks that are held together by strong chemical (covalent) bonds. The folding of this linear chain into a three-dimensional and functional shape or structure, however, is determined by a set of weaker non-covalent interactions. The common or traditional non-covalent interactions are hydrogen bonds, interactions between charged groups, and the hydrophobic effect. This project studies the interactions of carbon-hydrogen chemical groups with oxygens (C–H/O interactions) and with benzene-like amino acids (aromatic amino acids phenylalanine, tyrosine, and tryptophan) (C–H/pi interactions), as well as sulfur (from methionine and cysteine amino acids) with aromatic amino acids (S/pi interactions). Dr. Zondlo and coworkers aim to determine the chemical basis for what makes such interactions weak or strong at the atomic and subatomic levels both experimentally and by computation. Insights into these chemical principles for non-traditional non-covalent interactions are expeted to help explain the folding of proteins that are important in normal cellular activity, in cell division, and protein misfolding that can be important in dysfunctional biological systems or disease states such as Alzheimer's disease. This project provides multidisciplinary training to undergraduate and graduate students, including those from underserved communities. In addition, new discovery-oriented laboratory experiences are being developed to engage students in research within the undergraduate laboratory class.
This research examines the roles of chalcogen/pi, C–H/pi, and C–H/O interactions in protein structure. The interactions of amino acids containing sulfur with aromatic amino acids, including thiol-aromatic and methionine-aromatic interactions, have been observed in numerous contexts. Due to the relatively similar electronegativity of sulfur and selenium compared to carbon, the electrostatic basis for these interactions is expected to be relatively weak, particularly in water. The project uses a combination of small molecule synthesis, peptide synthesis, and protein expression to probe the nature of sulfur-aromatic interactions using x-ray crystallographic analysis of small molecules, biophysical methods (NMR, CD, IR) in peptides and proteins, functional analysis of proteins, and bioinformatics analysis. This work provides fundamental insights into the geometry and energetics of chalcogen-aromatic interactions and aims to identify particularly complementary pairwise combinations of chalcogen amino acids and aromatic amino acids that can be applied to molecular and supramolecular design. This work also seeks to identify protein motifs in which sulfur-aromatic interactions might be modulated by sulfur oxidation. The project will further explore protein motifs where C–H/O interactions are hypothesized to be central to protein structure, including roles of protein post-translational modifications in inducing structural changes via C–H/O interactions.
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.
