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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.

SUBMITTER: Wang SD

PROVIDER: S-EPMC8790752 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Individual DNA bases are known to be able to flip out of the helical stack, providing enzymes with access to the genetic information otherwise hidden inside the helix. Consequently, base flipping is a necessary first step to many more complex biological processes such as DNA transcription or replication. Much remains unknown about this elementary step, despite a wealth of experimental and theoretical studies. From the theoretical point of view, the involved timescale of milliseconds or longer requires the use of enhanced sampling techniques. In contrast to previous theoretical studies employing umbrella sampling along a predefined flipping coordinate, this study attempts to induce flipping without prior knowledge of the pathway, using information from a molecular dynamics simulation of a B-DNA fragment and the conformational flooding method. The relevance to base flipping of the principal components of the simulation is assayed, and a combination of modes optimally related to the flipping of the base through either helical groove is derived for each of the two bases of the central guanine-cytosine basepair. By applying an artificial flooding potential along these collective coordinates, the flipping mechanism is accelerated to within the scope of molecular dynamics simulations. The associated free energy surface is found to feature local minima corresponding to partially flipped states, particularly relevant to flipping in isolated DNA; further transitions from these minima to the fully flipped conformation are accelerated by additional flooding potentials. The associated free energy profiles feature similar barrier heights for both bases and pathways; the flipped state beyond is a broad and rugged attraction basin, only a few kcal/mol higher in energy than the closed conformation. This result diverges from previous works but echoes some aspects of recent experimental findings, justifying the need for novel approaches to this difficult problem: this contribution represents a first step in this direction. Important structural factors involved in flipping, both local (sugar-phosphate backbone dihedral angles) and global (helical axis bend), are also identified.

Project description:The crystal structure of Rad4/Rad23, the yeast homolog of the human nucleotide excision repair (NER) lesion recognition factor XPC-RAD23B ( Min , J. H. and Pavletich , N. P. ( 2007 ) Nature 449 , 570 - 575 ) reveals that the lesion-partner base is flipped out of the helix and binds to amino acids of the protein. This suggests the hypothesis that the flipping of this partner base must overcome a free energy barrier, which constitutes one element contributing to changes in the thermodynamic properties induced by the DNA damage and sensed by the recognition protein. We explored this hypothesis by computing complete flipping free energy profiles for two lesions derived from the procarcinogenic polycyclic aromatic hydrocarbons (PAHs), dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P), R-trans-anti-DB[a,l]P-N(6)-dA (R-DB[a,l]P-dA) and R-trans-anti-B[a]P-N(6)-dA (R-B[a]P-dA), and the corresponding unmodified duplex. The DB[a,l]P and B[a]P adducts differ in number and organization of their aromatic rings. We integrate these results with prior profiles for the R-trans-anti-DB[a,l]P-dG adduct ( Zheng , H. et al. ( 2010 ) Chem. Res. Toxicol. 23 , 1868 - 1870 ). All adopt conformational themes involving intercalation of the PAH aromatic ring system into the DNA duplex; however, R-DB[a,l]P-dA and R-B[a]P-dA intercalate from the major groove, while R-DB[a,l]P-dG intercalates from the minor groove. These structural differences produce different computed van der Waals stacking interaction energies between the flipping partner base with the lesion aromatic ring system and adjacent bases; we find that the better the stacking, the higher the relative flipping free energy barrier and hence lower flipping probability. The better relative NER susceptibilities correlate with greater ease of flipping in these three differently intercalated lesions. In addition to partner base flipping, the Rad4/Rad23 crystal structure shows that a protein-β-hairpin, BHD3, intrudes from the major groove side between the DNA strands at the lesion site. We present a molecular modeling study for the R-DB[a,l]P-dG lesion in Rad4/Rad23 showing BHD3 β-hairpin intrusion with lesion eviction, and we hypothesize that lesion steric effects play a role in the recognition of intercalated adducts.

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

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