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Article Written by the Salsbury Research Group Selected for Journal Cover

An article written by WFU Professor Freddie Salsbury and post-doc Lacramioara Negureanu has been selected for the cover of the February issue of the Journal of Biomolecular Structure and Dynamics.

The paper, "Insights into Protein - DNA Interactions, Stability and Allosteric Communications: A Computational Study of Mutsα-DNA Recognition Complexes" studies the conformational changes that occur in this recognition complex due to the binding of DNA damage from the chemotherapeutic cis-platin, in order to better understand the molecular origin of intra- and inter-protein communication mediated by this complex, to predict the effects of cancer-associated mutations on the molecular level, and to assist in further developing this complex as a target for therapeutic design.

The abstract of the paper follows: DNA mismatch repair proteins (MMR) maintain genetic stability by recognizing and repairing mismatched bases and insertion/deletion loops mistakenly incorporated during DNA replication, and initiate cellular response to certain types of DNA damage. Loss of MMR in mammalian cells has been linked to resistance to certain DNA damaging chemotherapeutic agents, as well as to increase risk of cancer. Mismatch repair pathway is considered to involve the concerted action of at least 20 proteins. The most abundant MMR mismatch-binding factor in eukaryotes, MutSα, recognizes and initiates the repair of base-base mismatches and small insertion/deletion. We performed molecular dynamics simulations on mismatched and damaged MutSα-DNA complexes. A comprehensive DNA binding site analysis of relevant conformations shows that MutSα proteins recognize the mismatched and platinum cross-linked DNA substrates in significantly different modes. Distinctive conformational changes associated with MutSα binding to mismatched and damaged DNA have been identified and they provide insight into the involvement of MMR proteins in DNA-repair and DNA-damage pathways. Stability and allosteric interactions at the heterodimer interface associated with the mismatch and damage recognition step allow for prediction of key residues in MMR cancer-causing mutations. A rigorous hydrogen bonding analysis for ADP molecules at the ATPase binding sites is also presented. Due to extended number of known MMR cancer causing mutations among the residues proved to make specific contacts with ADP molecules, recommendations for further studies on similar mutagenic effects were made.


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