Benjamin Kass, Meisel Lab & Haorong Li, Hao Lab, Graduate Students, GW Department of Chemistry
Fri, 16 September, 20222:00pm - 3:00pm
Benjamin Kass, Graduate Student, Meisel Lab, GW Department of Chemistry
Stereosequence-defined Aromatic Oligoamide Foldamers for Protein Surface Recognition presented by Benjamin Kass, Graduate Student, Meisel Lab, GW Department of Chemistry
Nature uses precise interactions between flat surfaces in innumerable protein-mediated processes, but most small molecule drugs neglect aiming for these exterior sites. Instead, medicinal chemistry is conditioned to binding compounds within deep pockets that exist only for a narrow subset of proteins, limiting the number of potential targets. In this work, we conversely direct our attention to proteins that lack such deep pockets by synthesizing aromatic oligoamide foldamers, chain molecules that fold into an ordered conformation in solution, that compliment and bind surface motifs. The shape of these oligomers is controlled by their stereosequence, the sequence of chiral monomers along the backbone. Several series of these compounds with unique stereosequences were synthesized using solid phase peptide coupling. Nuclear magnetic resonance and circular dichroism spectroscopy were used to compare the relative conformations of these oligomers in solution while single crystal x-ray diffraction was used to observe the hydrogen bonding pattern between dimers. We determined that the folding of these oligomers is primarily driven by the stereosequence and hydrogen bonding, demonstrating that configuration along the backbone is a major structural determinant in this scaffold. Diversification of the stereocentric functional groups show promise for improving both water solubility and specificity of interaction with proteins while maintaining conformational control.
Bio
Ben graduated Summa Cum Laude in Spring 2020 with dual B.S. degrees in biology and chemistry from the Honors College at Virginia Commonwealth University in his hometown of Richmond, VA. Not long after, he moved to Arlington, VA with his two cats to start his graduate career at The George Washington University, later joining the Meisel Lab and beginning work developing chiral peptide-mimicking scaffolds for biological recognition.
Haorong Li, Graduate Student, Hao Lab, GW Department of Chemistry
Integrated Proteomics and Metabolomics to Study Mitochondria in Neurodegenerative Diseases presented by Haorong Li, Graduate Student, Hao Lab, GW Department of Chemistry
Mitochondria produce most ATP via the oxidative phosphorylation (OXPHOS) pathway, a critical pathway that the brain relies on its energy need associated with its numerous functions, such as synaptic homeostasis and plasticity. Therefore, mitochondrial dysfunction is a prevalent pathological hallmark of many neurodegenerative disorders. My research focuses on providing novel knowledge of mitochondrial functions, dynamics, and disease-related pathways using various mass spectrometry (MS) based techniques.
The mitochondrial proteome is often overwhelmed by the much more complex whole cell proteome during MS analysis. Recent development in proximity labeling techniques allows enrichment of mitochondrial proteins of interest, their stable and transient protein interactors, and mitochondrial subcellular microenvironment. In proximity labeling, proteins of interest are biotinylated in situ, followed by in vitro streptavidin-based enrichment. However, major challenges include streptavidin contamination signals and lost information on protein biotinylation sites. We addressed these challenges by exploring thiol-cleavable biotin as a novel probe for proximity labeling.
Besides our affinity purification-based strategy, we reported metabolic fingerprints in fibroblasts derived from MELAS patients using integrated global proteomic and metabolomic analyses. MELAS is a progressive neurodegenerative disease that results in devastating multi-organ failure in childhood. MELAS is maternally inherited and caused by mitochondrial DNA pathogenic variants affecting the OXPHOS pathway, thereby leading to a chronic energy deficit. The genotype-phenotype relationship and pathogenic mechanism of MELAS remain elusive, which hampers the development of curative interventions. We conducted integrated proteomics and metabolomics experiments on patient-derived dermal fibroblasts to provide novel insights into the pathogenic pathways of MELAS.Our multi-omics approach revealed altered metabolic pathways in MELAS, such as the OXPHOS pathway, arginine biosynthesis, and bioenergetic pathways.
Bio
Haorong received his B.S. in Chemistry from China Agricultural University. He got his M.S. in Chemistry from Miami University. He then joined Dr. Ling Hao’s lab working on developing cleavable proximity labeling and multi-omics strategies to understand mitochondrial dysfunctions in neurodegenerative diseases.
