Journal:JBSD:31

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

Lacramioara Negureanu & Freddie Salsbury, Jr ^[1]

Molecular Tour
The DNA mismatch repair (MMR) pathway is one of the biochemical pathways that maintains genetic stability by recognizing and repairing DNA errors. In addition to their repair role, MMR proteins detect and initiate cell death in response to certain types of DNA damage, such as the crosslinking due to the chemotherapeutics cisplatin and carboplatin. The biochemical pathway(s) that connect the MMR proteins to the classic apoptotic proteins is incomplete, however, considerable experimental and computational work by the current authors and others have established the role of the human mismatch recognition factor MutSα in initiating this pathway(s) and have provided considerably detail as to how MutSα may respond to crosslinking due to cisplatin binding so to as to initiate these pathways. In this paper, we study the crosslinking due to carboplatin binding using molecular dynamics simulations. We report unique hydrogen bonding motifs associated with the recognition of this damage and different packing interactions at the protein-DNA interface, however, we also show that there are general features at the protein-DNA interface in binding of both cisplatin and carboplatin. Our simulations also indicate that the DNA is more disturbed by carboplatin; consistent with the available experimental evidence. Based on our simulations, we make specific predictions of key residues that should be relevant to the recognition of platinum-based damaged DNA adducts by MutSα, and others that may distinguish between the different damages