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Research Abstracts Online
January 2010 - March 2011

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University of Minnesota Twin Cities
College of Pharmacy
Department of Medicinal Chemistry

PI: Carston R. Wagner, Associate Fellow

Design and Modeling of Protein-Protein Interfaces 

In an effort to develop stable, self-assembled protein nanostructures, these researchers synthesized a homobifunctional small molecule consisting of two methotrexate molecules tethered together with a methylene linker (bis-MTX). This small molecule is capable of inducing the reversible dimerization of two dihydrofolate reductase (DHFR) monomers. Further expansion of this strategy led to the construction of similarly homobifunctional DHFR fusion proteins, tethered together with 1, 3, 7, and 13 amino acid linkers (1-, 3-, 7-, and 13DD, respectively). Treatment of DHFR fusion proteins with bis-MTX yields the formation of an assortment stable protein structures ranging from a dimeric protein "square” to larger, octameric protein nanorings. To exert a level of control over this protein assembly, the researchers sought to modulate protein dimer stability via the introduction of dimer interfacial mutations.

Group Members

Donald G. Truhlar, Co-Principal Investigator
Sanaa Bardaweel, Graduate Student
Matt Cuellar, Research Associate
Adrian Fegan, Research Associate
Amit Ganger, Graduate Student
Peter Huynh, Undergraduate Student
Yan Jia, Graduate Student
Brandie Kovaleski, Research Associate
Sidath Kumarapperuma, Research Associate
Qing Li, Graduate Student
Brian White, Graduate Student
Xin Xhou, Graduate Student