A perspective on the molecular simulation of DNA from structural and functional aspects

Mondal, Manas; Yang, Lijiang; Cai, Zhicheng; Patra, Piya; Gao, Yi Qin

doi:10.1039/d0sc05329e

Cited by 16 publications

(6 citation statements)

References 123 publications

(289 reference statements)

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“…Thus, the protonation state of cytosine bases helps to stabilize the stacked base pairs within the i-motif core at low pHs. It was found that an imino proton on the N3 atom of cytosine contributes to the formation of planar hydrogen-bonded hemiprotonated C:C + pairs, leading to base pairing that is stronger than classical Watson–Crick base pairing. , In the absence of a proton, cytosine bases can also form a pair through C:C W:W trans base pairing, where one cytosine base is shared along the base pair plane and forms two hydrogen bonds between the N4 atom of one cytosine and the N3 atom of another . We studied the conformational preference and base pairing of closely interacting cytosine bases in the i-motif core at different pHs.…”

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confidence: 99%

Microscopic Insight into pH-Dependent Conformational Dynamics and Noncanonical Base Pairing in Telomeric i-Motif DNA

Mondal

Gao

2022

J. Phys. Chem. Lett.

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Gene regulatory functions of noncanonical i-motif DNA are associated with dynamic i-motif formation in the cellular environment and pH variation. With atomistic simulations, we show the dramatic influence of solvent pH on the conformational dynamics of biologically relevant telomeric i-motif DNA coupled with protonation of cytosine bases in different conformations. We rationalized the pHdependent dynamics and conformational variability of the i-motif in terms of base pairing and specific loop motions. The human telomeric i-motif is found to acquire various metastable folded conformations at pH values near the pK a of cytosine with the formation of a noncanonical C:C W:W trans base pair along with the hemiprotonated C:C + pairs in the i-motif core. pH-dependent dynamics and the local solvent structure of i-motif DNA imply that the presence of a cosolvent or molecular crowding can promote i-motif formation in vivo by changing the conformational fluctuations and hydration state of the structure.

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confidence: 99%

Microscopic Insight into pH-Dependent Conformational Dynamics and Noncanonical Base Pairing in Telomeric i-Motif DNA

Mondal

Gao

2022

J. Phys. Chem. Lett.

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“…3,4 An MD simulation yields a molecular time trace that can complement experiments by either aiding in interpretation or providing predictions. MD simulations allow studying a wide range of molecular phenomena relevant to biomolecular systems, [5][6][7] and can increase the accessibility of processes that, to date, cannot be observed in experiments, such as the relaxation of DNA to a specific ionic environment. [8][9][10][11] Tailored strategies for modeling reaction mechanisms of ligands interacting with DNA can utilize MD simulations.…”

Section: Introductionmentioning

confidence: 99%

Enhanced sampling strategies for molecular simulation of DNA

Mohr,

van Heesch,

Pérez de Alba Ortíz

et al. 2024

WIREs Comput Mol Sci

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Molecular dynamics (MD) simulations can provide detailed insights into complex molecular systems, such as DNA, at high resolution in space and time. Using current computer architectures, time scales of tens of microseconds are feasible with contemporary all‐atom force fields. However, these timescales are insufficient to accurately characterize large conformational transitions in DNA and compare calculations to experimental data. This review discusses the advantages and drawbacks of two simulation approaches to overcome the timescale challenge. The first approach is based on adding biasing potentials to the system to drive transitions. Umbrella sampling, steered MD, and metadynamics are examples of these methods. A key challenge of such methods is the necessity of selecting one or a few efficient coordinates, commonly referred to as collective variables (CVs), along which to apply the biasing potential. The path‐metadynamics methodology addresses this issue by finding the optimal route(s) between states in a multi‐dimensional CV space. The second strategy is path sampling, which focuses MD simulations on the transitions. The assumption is that even though transitions between states are rare, they are generally fast. Stopping the simulations as soon as they reach a stable state can significantly increase simulation efficiency. We introduce these methods on the two‐dimensional Müller–Brown potential. DNA applications are featured for two different processes: the Watson–Crick–Franklin to Hoogsteen transition in adenine–thymine base pairs and the binding of a DNA‐binding protein domain to DNA.This article is categorized under: Molecular and Statistical Mechanics Molecular Dynamics and Monte‐Carlo Methods Molecular and Statistical Mechanics Free Energy Methods Software Simulation Methods

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“… 8 − 10 Therefore, accurate information about base flip dynamics is of high interest and importance. 10 , 11 …”

Section: Introductionmentioning

confidence: 99%

“…8−10 Therefore, accurate information about base flip dynamics is of high interest and importance. 10,11 Thymine glycol (5,6-dihydro-5,6-dihydroxy thymine; Tg) is the most common oxidation product of thymine. Approximately 400 Tg residues are formed in a normal cell each day, and 10−20% of genome damages have been attributed to the oxidative conversion of thymine to Tg.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Base flipping may even be linked to early events in the opening and unwinding of DNA for transcription and replication processes . Although extensive studies have found that many DNA repair/modification proteins completely flip their target base out extrahelically, it is still under debate whether the base flipping occurs spontaneously or not. − Therefore, accurate information about base flip dynamics is of high interest and importance. , …”

Section: Introductionmentioning

confidence: 99%

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

Wang

Eriksson

Zhang

2022

J. Chem. Inf. Model.

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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.

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A perspective on the molecular simulation of DNA from structural and functional aspects

Abstract: An overview of atomistic simulations on the effect of sequences, base modifications, environmental factors and protein binding on DNA’s hierarchical structure and dynamics in the context of protein–DNA interactions, gene regulation and structural organization of chromatin.

Cited by 16 publications

References 123 publications

Microscopic Insight into pH-Dependent Conformational Dynamics and Noncanonical Base Pairing in Telomeric i-Motif DNA

Microscopic Insight into pH-Dependent Conformational Dynamics and Noncanonical Base Pairing in Telomeric i-Motif DNA

Enhanced sampling strategies for molecular simulation of DNA

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

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