Dynamics of 5R-Tg Base Flipping in DNA Duplexes Based on Simulations─Agreement with Experiments and Beyond

Abstract

Damaged or mismatched DNA bases are normally thought to be able to flip out of the helical stack, providing enzymes with access to the faulty genetic information otherwise hidden inside the helix. Thymine glycol (Tg) is one of the most common products of nucleic acid damage. However, the static and dynamic structures of DNA duplexes affected by 5R-Tg epimers are still not clearly understood, including the ability of these to undergo spontaneous base flipping. Structural effects of the 5R-Tg epimers on the duplex DNA are herein studied using molecular dynamics together with reliable DFT based calculations. In comparison with the corresponding intact DNA, the cis -5R,6S-Tg epimer base causes little perturbation to the duplex DNA, and a barrier of 4.9 kcal mol –1 is obtained by meta-eABF for cis -5R,6S-Tg base flipping out of the duplex DNA, comparable to the 5.4 kcal mol –1 obtained for the corresponding thymine flipping in intact DNA. For the trans -5R,6R-Tg epimer, three stable local structures were identified, of which the most stable disrupts the Watson–Crick hydrogen-bonded G5/C20 base pair, leading to conformational distortion of the duplex. Interestingly, the relative barrier height of the 5R-Tg flipping is only 1.0 kcal mol –1 for one of these trans -5R,6R-Tg epimers. Water bridge interactions were identified to be essential for 5R-Tg flipping. The study clearly demonstrates the occurrence of partial trans -5R,6R-Tg epimer flipping in solution.

Synthetic DNA binders for fluorescent sensing of thymine glycol-containing DNA duplexes and inhibition of endonuclease activity

“…2 It has been estimated that 400 Tg residues are formed in a normal cell each day, and 10-20% of DNA damages are attributed to the oxidative conversion of thymine to Tg. 3 Given its importance in understanding cellular oxidative stress and diagnostic applications, 2,4 much attention has been paid to the development of analytical methods for the detection of Tg residues.…”