Non-specificity and synergy at the binding site of the carboplatin-induced DNA adduct via molecular dynamics simulations of the MutS?-DNA recognition complex.

ABSTRACT: MutS? is the most abundant mismatch-binding factor of human DNA mismatch repair (MMR) proteins. MMR maintains genetic stability by recognizing and repairing DNA defects. Failure to accomplish their function may lead to cancer. In addition, MutS? recognizes at least some types of DNA damage making it a target for anticancer agents. Here, complementing scarce experimental data, we report unique hydrogen-bonding motifs associated with the recognition of the carboplatin induced DNA damage by MutS?. These data predict that carboplatin and cisplatin induced damaging DNA adducts are recognized by MutS? in a similar manner. Our simulations also indicate that loss of base pairing at the damage site results in (1) non-specific binding and (2) changes in the atomic flexibility at the lesion site and beyond. To further quantify alterations at MutS?-DNA interface in response to damage recognition, non-bonding interactions and salt bridges were investigated. These data indicate (1) possible different packing and (2) disruption of the salt bridges at the MutS?-DNA interface in the damaged complex. These findings (1) underscore the general observation of disruptions at the MutS?-DNA interface and (2) highlight the nature of the anticancer effect of the carboplatin agent. The analysis was carried out from atomistic simulations.

SUBMITTER: Negureanu L 

PROVIDER: S-EPMC3884054 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature