Acetylation of lysine residues, one of the most common protein post-transcriptional modifications, is thought to regulate protein affinity with other proteins or nucleotides. Experimentally, the effects of acetylation have been studied using recombinant mutants in which lysine residues (K) are substituted with glutamine (Q) as a mimic of acetyl lysine (KQ mutant), or with arginine (R) as a mimic of nonacetylated lysine (KR mutant). These substitutions, however, have not been properly validated. The effects lysine acetylation on Ku, a multifunctional protein that has been primarily implicated in DNA repair and cell survival, are characterized herein using a series of computer simulations. The binding free energy was reduced in the KQ mutant, while the KR mutant had no effect, which is consistent with previous experimental results. Unexpectedly, the binding energy between Ku and DNA was maintained at almost the same level as in the wild type protein despite full acetylation of the lysine residues. These results suggest that the effects of acetylation may be overestimated when the KQ mutant is used as a mimic of the acetylated protein.

Classical molecular dynamics methods were used to analyze the importance of 8-oxoguanine (8-oxoG) pairing with other DNA bases in order to determine the impact of oxidative guanine lesions on DNA structure. Six lesioned molecules, each containing 8-oxoG mispaired with one of the four normal bases on the the opposite strand at the center of 40-mer DNA, and one non-damaged DNA molecule, were simulated for 2 nanoseconds of real time. The 8-oxoG lesioned bases were found to incorporate opposite all normal bases. There are observed conformational and energetical differences among these parings. 8-oxoG in anti-form creates firm hydrogen bonds with cytosine and this bonding has a strong attractive electrostatic interaction energy similar to that of a native base pair-guanine to cytosine. Meanwhile, it does not form a stable base pair with purine bases (adenine and guanine) nor with the pyrimidine base thymine. On the other hand, the 8-oxoG in syn-form was found to pair with adenine.

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This work highlights four different topics in modeling of DNA: (i) the importance of water and ions together with the structure and function of DNA; the hydration structure around the ions appears to be the determining factor in the ion coordination to DNA, as demonstrated in the results of our MD simulations; (ii) how MD simulations can be used to simulate single molecule manipulation experiments as a complement to reveal the structural dynamics of the studied biomolecules; (iii) how damaged DNA can be studied in computer simulations; and (iv) how repair of damaged DNA can be studied theoretically.