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. MutSalpha consists of Msh2 (colored in green) and Msh6 (is in magenta). Click here to see MutSα-DNA complex structural model. DNA is shown in cyan. The color code for the heterodimer domains is as following: red for the mismatch binding domain, residues 1 to 124 in Msh2 and 1 to 157 in Msh6; yellow for the connector domain, residues 125 to 297 in MSH2 and 158 to 356 in Msh6; green for the lever domain, residues 300 to 456 and 554 to 619 in Msh2, and 357 to 573 and 648 to 714 in Msh6; magenta for the clamp domain, residues 457 to 553 in Msh2 and 574 to 647 in Msh6; blue for the ATPase domain, residues 620 to 855 in Msh2 and 715 to 974 in Msh6.

Click here to see global view of the 1,3 platinum-DNA adduct by Msh2 and Msh6. Msh2 colored in green and Msh6 is in magenta, respectively. DNA is shown in cyan with the damaged bases are in salmon. The residues that interact with DNA are shown as spheres, residues that form hydrogen bonds are labeled. Platinum is shawn as sphere and colored in royalblue