Amino acids and nucleic acids are often called the “Building Blocks of Life” because they are the monomeric units of large biomolecules, proteins and DNA. As each one of these building blocks has unique chemical properties with the potential to interact with other building blocks in specific and predictable ways, we can use these molecular interaction rules to design simple biomolecular systems. The long-term research goal of my research group is to combine these known molecular interaction rules in an effort to design responsive biomaterials. I am currently designing responsive biomaterials from two different approaches: 1) combining nucleic acid recognition with simple peptide self-assembly motifs and 2) incorporating the dynamic covalent chemistry of disulfide bonds with β-sheet forming peptides. For every generation of modified peptides that my group studies, the research work falls into, first, the synthesis and purification of the constructs, and, secondly, assembly and characterization of the resulting supramolecular structures. Since setting my laboratory up in Fall 2015, my students and I have successfully synthesized, purified, assembled and characterized the first generation of modified peptides for both projects.
Research Projects
The nucleopeptide system is a synthetic chimera library composed of a modified guanosine nucleoside conjugated to different dipeptides, including phenylalanine-phenylalanine. Both guanosine and phenylalanine-phenylalanine supramolecular structures have been individually studied at length. The electron-rich nucleopeptides will be studied for emergent electronic properties.
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The dithiolane-modified peptide system functionalizes the N-terminus of a self-assembling peptide with a 1,2-dithiolane molecule (lipoic acid and asparagusic acid). While β-sheet forming peptides are assembled and stabilized by non-covalent interactions amongst individual peptides, these 1,2-dithiolane-modified peptides are capable of forming covalent disulfide bonds between each other under appropriate conditions (response to pH and light). In addition to using the dithiolane dynamic covalent chemistry to stabilize supramolecular structures, there is great potential to use the reactive and accessible surface thiols to construct functional nanodevices.
The lessons that were learned from the 1,2-dithiolane project, led us to start exploring dynamic covalent chemistry reactivity on supramolecular surfaces. We have shown that a thiol-thioester exchange reaction can occur on the nano fiber surface to reveal reactive thiols. We brielle this strategy will expand the current methods and applications of post-assembly modification of supramolecular structures.
Collaborative Research Projects
Self-assembling peptides for Electrochemical Sensing Applications: In collaboration with Prof. Amanda Harper-Leatherman, we are studying the incorporation of self-assembly peptides in a layered electrochemical sensing scheme for uric acid detection.
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Samantha Brown ('19) and Jon Myers ('19) explain the project in the video below:
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Insulin-degrading enzyme Project: Insulin-degrading enzyme (IDE) is a Zn2+ metalloproteinase that degrades proteins such as insulin and amyloid beta. Our project aims to analyze various functional requirements of the IDE active site residues that affect substrate binding, specificity and proteolysis using a mutational analysis of bacterially expressed human IDE and kinetic studies using fluorogenic resonance energy transfer (FRET) derivatives of human insulin and amyloid-beta peptides. The cloning, expression and purification of human IDE and IDE mutants was accomplished by our collaborators in Prof. Alper’s laboratory at Sacred Heart University. Kinetic assays and proteolytic cleavage site mapping using MALDI-TOF mass spectrometry and post-source decay sequencing were performed to analyze substrate binding, specificity and proteolysis. The results from our studies will better define the functional conditions for the conservation of hydrophobic and aromatic IDE active site residues, which aid in proteolysis. Using this study’s findings may prove beneficial in designing IDE inhibitors or by engineering various mutant forms of human insulin that alter the rate of IDE proteolysis.
Funding
Fairfield University Faculty Research Committee Grant, Co-Investigator “Electrochemical Characterization of Self-Assembling Peptides” (2020)
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National Science Foundation Major Research Instrumentation (MRI), Co-Investigator “Acquisition of a 400 MHz NMR Spectrometer at Fairfield University” (2018)
NASA Connecticut Space Grant Consortium Faculty Research Grant, Principle Investigator “Characterization of Dithiolane-Modified Self-Assembly Structures” (2016)
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National Science Foundation Major Research Instrumentation (MRI), Principle Investigator “Acquisition of a MALDI-TOF Mass Spectrometer at Fairfield University” (2016)
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Fairfield University Science Institute grant, Principle Investigator “Characterizing the pH responsiveness of dithiolane-modified peptide self-assembly structures” (2016)
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Fairfield University Science Institute grant, Co-Investigator “Fairfield University undergraduate student poster presentation and attendance at the American Chemical Society National Meeting” (2016)
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Fairfield University Faculty Research Committee Grant, Principle Investigator “Isotope-Edited FT-IR analysis of dithiolane-modified peptide self-assembly structures” (2016)