Quantum chemistry investigation of a ubiquitin-transfer reaction coordinate
Format
Oral Presentation
Faculty Mentor Name
Anthony D. Dutoi
Faculty Mentor Department
Chemistry
Additional Faculty Mentor Name
Joseph S. Harrison
Additional Faculty Mentor Department
Department of Chemistry
Abstract/Artist Statement
Ubiquitin is a eukaryotic protein that participates in many crucial functions, ranging from the degradation of proteins to the regulation of enzymes. Ubiquitin performs its role by tagging target molecules, where different polyubiquitin chain formations indicate different functions to be carried out. Thus, it is important to investigate and understand the mechanism by which ubiquitin becomes attached to a target molecule. The attachment of ubiquitin is generally facilitated by three families of proteins: E1, E2, and E3. Through crystal structures and computer models, the site of the final ubiquitin transfer is already known to involve the amine end of a lysine on the target protein, and the thioester linkage of a ubiquitin–E2 complex. However, much remains unknown about this process, such as the optimal position for the attacking nucleophile on the lysine and the conformation around the thioester electrophile. We use quantum chemical calculations to evaluate the energy and visualize the molecular orbitals for different arrangements of small-molecule models of the lysine and thioester. Our investigation has found that there are significant changes in the binding energy when the dihedral angle of the methyl group attached to the sulfur on the thioester is changed. Most notable is the enhanced binding at 270°, relative to the carbonyl oxygen. This is a potential indicator for the optimal conformation that the protein must enforce during the process of ubiquitin tagging.
Location
Sierra Learning Lab, William Knox Holt Memorial Library and Learning Center
Start Date
30-4-2022 10:00 AM
End Date
30-4-2022 10:19 AM
Quantum chemistry investigation of a ubiquitin-transfer reaction coordinate
Sierra Learning Lab, William Knox Holt Memorial Library and Learning Center
Ubiquitin is a eukaryotic protein that participates in many crucial functions, ranging from the degradation of proteins to the regulation of enzymes. Ubiquitin performs its role by tagging target molecules, where different polyubiquitin chain formations indicate different functions to be carried out. Thus, it is important to investigate and understand the mechanism by which ubiquitin becomes attached to a target molecule. The attachment of ubiquitin is generally facilitated by three families of proteins: E1, E2, and E3. Through crystal structures and computer models, the site of the final ubiquitin transfer is already known to involve the amine end of a lysine on the target protein, and the thioester linkage of a ubiquitin–E2 complex. However, much remains unknown about this process, such as the optimal position for the attacking nucleophile on the lysine and the conformation around the thioester electrophile. We use quantum chemical calculations to evaluate the energy and visualize the molecular orbitals for different arrangements of small-molecule models of the lysine and thioester. Our investigation has found that there are significant changes in the binding energy when the dihedral angle of the methyl group attached to the sulfur on the thioester is changed. Most notable is the enhanced binding at 270°, relative to the carbonyl oxygen. This is a potential indicator for the optimal conformation that the protein must enforce during the process of ubiquitin tagging.