Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

Shifting interfaces: changes in protein-protein and protein-DNA interfaces probed via molecular dynamics

Over the past decade, there has been a growing interest in studying the binding of DNA to the MutSalpha protein complex. This heterodimeric protein complex, the Msh2/Msh6 complex in humans, is the initial complex that binds mismatched DNA and other DNA defects that occur during replication. This complex has also been shown to bind at least some types of damaged DNA, such as the cross-linked adducts due to the chemotherapeutics cisplatin and carboplatin, or the incorporation of the chemotherapeutic, FdU. As a result of this interest, multiple studies have contrasted the interactions of MutSalpha with its normal mismatched substrate and with the interactions of MutsSalpha to DNA damaged by the chemotherapeutic cisplatin. To complement these studies, we examine the interaction between MutSalpha and DNA damaged by carboplatin via all-atom molecular dynamics simulations. These simulations provide evidence for subtle changes in the protein/DNA and protein/protein interfaces. The interfaces shifts found are broadly similar to those found in binding to the adduct from cis-platin, but have distinct differences. These subtle differences may play a role in the way the different damages and mismatched DNA are signaled by MutSalpha, and suggest a signaling mechanism for DNA damage that chiefly involves shifts in protein-protein interactions as opposed to changes in protein conformation.



  1. L. Negureanu and F. R. Salsbury Jr. “Insights into Protein-DNA Interactions, Stability and Allosteric Communications: A Computational Study of Mutsalpha-DNA Recognition Complexes.” Journal of Biomolecular Structure & Dynamics, 29:4 757-779 (2012)

  2. L. Negureanu and F. R. Salsbury Jr. “The molecular origin of the MMR-dependent apoptosis pathway from dynamics analysis of the MutSalpha-DNA complexes.” Journal of Biomolecular Structure & Dynamics, 30:3 347-361 (2012)

  3. F. R. Salsbury Jr., J. E. Clodfelter, M. B. Gentry, T. Hollis and K. D. Scarpinato “The molecular mechanism of DNA damage recognition by MutS homologs and its consequences for cell death response.” Nucleic Acids Research, 34:9 2173-2185 (2006)

Lacra Negureanu
Freddie Salsbury Jr.

Department of Physics
Wake Forest University Winston-Salem, NC 27109

Ph: 336-58-4975