Title

Quantum chemistry investigation of a ubiquitin-transfer reaction coordinate

Lead Author Major

Pre-Dentistry

Lead Author Status

Sophomore

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

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Apr 30th, 10:00 AM Apr 30th, 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.