Markov state models elucidate the stability of DNA influenced by the chiral 5S-Tg base

Wang, Shu dong; Zhang, Rubo; Eriksson, Leif A.

doi:10.1093/nar/gkac691

Cited by 4 publications

(2 citation statements)

References 60 publications

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“…8(d)). We noticed that among all these parameters, the deviation of X-disp and Inclin are the most important factors affecting base ipping, which is consistent with our previous research [46,47] . Additionally, the minor groove are 10.2 Å for both A-DNA1 and A-DNA2, while it is only 7.3 and 6.9 Å for both B-DNA1 and B-DNA2, respectively.…”

Section: The Structural Featuressupporting

confidence: 92%

The base flipping of A-DNA—a molecular dynamic simulation study

Wang,

Zheng,

2024

Struct Chem

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Due to different solvent conditions, double helix DNA exists in various conformations, such as B-DNA, A-DNA, C-DNA and Z-DNA. Recent studies have found that A-DNA is present in complexes with proteins, and has an important biological role in the context of cellular defense mechanisms under harsh conditions. In this study, the well-tempered meta-dynamics (WTM-eABF) were used to explore the free energy barriers for base ipping of the four natural bases, Adenine, Guanine, Cytosine, and Thymine in both A-form and B-form DNA duplex. The results show that the free energy barriers for base ipping was lower in A-DNA than that in B-DNA for all of the four natural bases. We analyzed the factors that may affect base ipping, such as π-π stacking, SASA, and conformational changes, and proved that conformational changes and π-π stacking are the most important factors affecting base ipping.

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Section: The Structural Featuressupporting

confidence: 92%

The base flipping of A-DNA—a molecular dynamic simulation study

Wang,

Zheng,

2024

Struct Chem

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“…As for other DNA repair enzymes, − computational work has provided insights into the mechanism of action of MutY, but has also raised new questions. ,,, Indeed, ONIOM (QM:QM) calculations initiated from the FLRC MutY crystal structure provided additional support for the critical and distinct roles of E43 and D144 . Furthermore, this work was the first to identify a catalytic role for Y126, namely charge stabilization and positioning of E43, and proposed that D144 explicitly catalyzes nucleobase dissociation by undergoing partial nucleophilic attack of the sugar .…”

Section: Introductionmentioning

confidence: 99%

Distinctive Formation of a DNA–Protein Cross-Link during the Repair of DNA Oxidative Damage: Insights into Human Disease from MD Simulations and QM/MM Calculations

Nikkel

Wetmore

2023

J. Am. Chem. Soc.

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Reactive oxygen species damage DNA and result in health issues. The major damage product, 8-oxo-7,8-dihydroguanine (8oG), is repaired by human adenine DNA glycosylase homologue (MUTYH). Although MUTYH misfunction is associated with a genetic disorder called MUTYH-associated polyposis (MAP) and MUTYH is a potential target for cancer drugs, the catalytic mechanism required to develop disease treatments is debated in the literature. This study uses molecular dynamics simulations and quantum mechanics/molecular mechanics techniques initiated from DNA−protein complexes that represent different stages of the repair pathway to map the catalytic mechanism of the wild-type MUTYH bacterial homologue (MutY). This multipronged computational approach characterizes a DNA−protein cross-linking mechanism that is consistent with all previous experimental data and is a distinct pathway across the broad class of monofunctional glycosylase repair enzymes. In addition to clarifying how the cross-link is formed, accommodated by the enzyme, and hydrolyzed for product release, our calculations rationalize why cross-link formation is favored over immediate glycosidic bond hydrolysis, the accepted mechanism for all other monofunctional DNA glycosylases to date. Calculations on the Y126F mutant MutY highlight critical roles for active site residues throughout the reaction, while investigation of the N146S mutant rationalizes the connection between the analogous N224S MUTYH mutation and MAP. In addition to furthering our knowledge of the chemistry associated with a devastating disorder, the structural information gained about the distinctive MutY mechanism compared to other repair enzymes represents an important step for the development of specific and potent small-molecule inhibitors as cancer therapeutics.

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Mechanism of Dual-Site Recognition in a Classic DNA Aptamer

Wang,

Eriksson,

Zhang

2024

J. Chem. Inf. Model.

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Nucleic acid aptamers possess unique advantages in specific recognition. However, the lack of in-depth investigation into their dynamic recognition mechanisms has restricted their rational design and potential applications in fields such as biosensing and targeted therapy. We herein utilized enhanced sampling molecular dynamics to address affinities of adenosine monophosphate (AMP) to the dual binding sites in the DNA aptamer, focusing on the dynamic recognition mechanism and pathways. The present results indicate that in addition to the widely known intermolecular interactions, inequivalence of chemical environments of the two binding sites leads to slightly higher stability of AMP binding to the site proximal to the aptamer terminus. In the presence of two AMPs captured by the two sites, each binding free energy is enhanced. In particular, an additional hydrogen bond of AMP to A10 is introduced in the dual-site binding complex, which increases the binding energy from −4.25 ± 0.47 to −9.48 ± 0.33 kcal mol −1 in the site close to the loop. For the dual-site recognition process, the free energy landscape and minimum free energy pathway calculations elucidate the crucial role of electrostatic interactions between the AMP phosphate groups and Na + ions in positively cooperative binding mechanisms.

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Markov state models elucidate the stability of DNA influenced by the chiral 5S-Tg base

Cited by 4 publications

References 60 publications

The base flipping of A-DNA—a molecular dynamic simulation study

The base flipping of A-DNA—a molecular dynamic simulation study

Distinctive Formation of a DNA–Protein Cross-Link during the Repair of DNA Oxidative Damage: Insights into Human Disease from MD Simulations and QM/MM Calculations

Mechanism of Dual-Site Recognition in a Classic DNA Aptamer

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