A simulation study of the binding modes of formamido-pyrimidine bound to DNA containing 8-oxo guanine

COMP 206

Kun Song1, Arthur P. Grollman, apg@pharm.sunysb.edu2, Carlos de los Santos, cds@pharm.sunysb.edu3, and Carlos Simmerling, carlos@csb.sunysb.edu1. (1) Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, (2) Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-8651, (3) Department of Pharmacology, Stony Brook University, Stony Brook, NY 11790
8-oxo guanine (8OG) is the most common form of the oxidative DNA damage. Failure to repair this damage can cause G to T transversions. In E. coli and other bacteria this damage is repaired by formamido-pyrimidine DNA glycosylase (MutM or Fpg). Currently there are two theories about how MutM recognizes the damaged base, which are supported by experimental and simulation studies. The key difference between these two theories is the conformation of the 8OG. We studied the mutation's effects on the conformations of the residues neighboring the active site and the two binding modes of the wild type systems using the molecular dynamics simulations and energy decomposition analysis. Our study suggests that the 8OG's syn conformation seen in the experimental studies is correct, but the details of the binding differ due to the E2Q mutation.