Dataset Information

Redox-Based Defect Detection in Packed DNA: Insights from Hybrid Quantum Mechanical/Molecular Mechanics Molecular Dynamics Simulations.

ABSTRACT: The impact of an 8-oxoguanine (8oxoG) defect on the redox properties of DNA within the nucleosome core particle (NCP) was investigated employing hybrid quantum mechanical/molecular mechanics (QM/MM) molecular dynamics simulations of native and 8oxoG-containing NCP systems with an explicit representation of a biologically relevant environment. Two distinct NCP positions with varying solvent accessibility were considered for 8oxoG insertion. In both cases, it is found that the presence of 8oxoG drastically decreases the redox free energy of oxidation by roughly 1 eV, which is very similar to what was recently reported for free native and 8oxoG-containing DNA. In contrast, the effect of 8oxoG on the reorganization free energy is even smaller for packed DNA (decrease of 0.13 and 0.01 eV for defect-free and defect-containing systems, respectively) compared to the one for free DNA (0.25 eV), consistent with the increased rigidity of the NCP as compared to free DNA. Furthermore, the presence of an 8oxoG defect does not yield any significant changes in the packed DNA structure. Such a conclusion favors the idea that in the case of chromatin, defect-induced changes in DNA redox chemistry can also be exploited to detect damaged bases via DNA-mediated hole transfer.

SUBMITTER: Kılıc M

PROVIDER: S-EPMC10687876 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Redox-Based Defect Detection in Packed DNA: Insights from Hybrid Quantum Mechanical/Molecular Mechanics Molecular Dynamics Simulations.

Kılıç Murat M Diamantis Polydefkis P Johnson Sophia K SK Toth Oliver O Rothlisberger Ursula U

Journal of chemical theory and computation 20231114 22

The impact of an 8-oxoguanine (8oxoG) defect on the redox properties of DNA within the nucleosome core particle (NCP) was investigated employing hybrid quantum mechanical/molecular mechanics (QM/MM) molecular dynamics simulations of native and 8oxoG-containing NCP systems with an explicit representation of a biologically relevant environment. Two distinct NCP positions with varying solvent accessibility were considered for 8oxoG insertion. In both cases, it is found that the presence of 8oxoG dr ...[more]

PMID: 37963372

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Project description:Direct molecular dynamics (MD) simulation with ab initio quantum mechanical and molecular mechanical (QM/MM) methods is very powerful for studying the mechanism of chemical reactions in a complex environment but also very time-consuming. The computational cost of QM/MM calculations during MD simulations can be reduced significantly using semiempirical QM/MM methods with lower accuracy. To achieve higher accuracy at the ab initio QM/MM level, a correction on the existing semiempirical QM/MM model is an attractive idea. Recently, we reported a neural network (NN) method as QM/MM-NN to predict the potential energy difference between semiempirical and ab initio QM/MM approaches. The high-level results can be obtained using neural network based on semiempirical QM/MM MD simulations, but the lack of direct MD samplings at the ab initio QM/MM level is still a deficiency that limits the applications of QM/MM-NN. In the present paper, we developed a dynamic scheme of QM/MM-NN for direct MD simulations on the NN-predicted potential energy surface to approximate ab initio QM/MM MD. Since some configurations excluded from the database for NN training were encountered during simulations, which may cause some difficulties on MD samplings, an adaptive procedure inspired by the selection scheme reported by Behler [ Behler Int. J. Quantum Chem. 2015 , 115 , 1032 ; Behler Angew. Chem., Int. Ed. 2017 , 56 , 12828 ] was employed with some adaptions to update NN and carry out MD iteratively. We further applied the adaptive QM/MM-NN MD method to the free energy calculation and transition path optimization on chemical reactions in water. The results at the ab initio QM/MM level can be well reproduced using this method after 2-4 iteration cycles. The saving in computational cost is about 2 orders of magnitude. It demonstrates that the QM/MM-NN with direct MD simulations has great potentials not only for the calculation of thermodynamic properties but also for the characterization of reaction dynamics, which provides a useful tool to study chemical or biochemical systems in solution or enzymes.

Dataset Information

Redox-Based Defect Detection in Packed DNA: Insights from Hybrid Quantum Mechanical/Molecular Mechanics Molecular Dynamics Simulations.

Publications

Redox-Based Defect Detection in Packed DNA: Insights from Hybrid Quantum Mechanical/Molecular Mechanics Molecular Dynamics Simulations.

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