Molecular dynamics simulations of DNA repair protein MutS and DNA complexes

分子動力学シミュレーションによるDNA修復誘導タンパク質MutS-DNA複合体の動的解析

石田 恒

Ishida, Hisashi

DNA mismatch repair (MMR) maintains genome stability by repairing mismatches that arise through DNA replication errors and during recombination. Defects in MMR result in a significant increase in the spontaneous mutation rate and predispose humans to cancer. In E. coli, the proteins MutS, MutL and MutH are responsible for the MMR. MMR is initiated by MutS, which functions in the homodimer form. MutS recognizes and efficiently binds to mispaired bases and unpaired bases in DNA duplexes. It is thought that the ATPase activity of MutS plays a role in proofreading to verify mismatch binding and authorize the following downstream excision in which MutL and MutS are involved. In order to investigate how the binding of MutS to the DNA and ATP hydrolysis are coordinated, molecular dynamics (MD) simulations of the wild-type and mutant MutS in water with mismatched and undamaged DNA were performed. Including the water molecules, each system comprised about 200,000 atoms. The MD simulations were carried out at a constant pressure of one bar and a temperature of 300 K for several tens of nanoseconds in total. The binding free energies were calculated using the MM-GBSA method, and the results are consistent with the experimental data. Moreover, the dynamic relationship between the DNA biding and ATPase domain sites was analyzed.