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.