Modeling DNA Flexibility: Comparison of Force Fields from Atomistic to Multiscale Levels

Minhas, Vishal; Sun, Tiedong; Mirzoev, Alexander; Korolev, Nikolay; Lyubartsev, Alexander P.; Nordenskiöld, Lars

doi:10.1021/acs.jpcb.9b09106

Cited by 41 publications

(64 citation statements)

References 70 publications

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“…DNA can be described by several force fields such as parmbsc1 ( 38 ), parmOL15 ( 39 ), CHARMM27 ( 40 , 41 ), and CHARMM36 ( 42 ). Since recent benchmarks showed similar performance of parmbsc1 and parmOL15 ( 43–45 ) and overall better reliability than CHARMM force fields ( 44 , 46 , 47 ), we employed parmbsc1 in this work. Each DNA was immersed into a truncated octahedral box filled by the TIP3P water, ( 48 ) and 24 (class I ) or 28 (classes II, III, C1, C2, H1, H2, H3 ) sodium ( 49 ) cations to maintain electroneutrality.…”

Section: Methodsmentioning

confidence: 99%

Importance of base-pair opening for mismatch recognition

Bouchal

Durník

Illík

et al. 2020

Nucleic Acids Research

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Mismatch repair is a highly conserved cellular pathway responsible for repairing mismatched dsDNA. Errors are detected by the MutS enzyme, which most likely senses altered mechanical property of damaged dsDNA rather than a specific molecular pattern. While the curved shape of dsDNA in crystallographic MutS/DNA structures suggests the role of DNA bending, the theoretical support is not fully convincing. Here, we present a computational study focused on a base-pair opening into the minor groove, a specific base-pair motion observed upon interaction with MutS. Propensities for the opening were evaluated in terms of two base-pair parameters: Opening and Shear. We tested all possible base pairs in anti/anti, anti/syn and syn/anti orientations and found clear discrimination between mismatches and canonical base-pairs only for the opening into the minor groove. Besides, the discrimination gap was also confirmed in hotspot and coldspot sequences, indicating that the opening could play a more significant role in the mismatch recognition than previously recognized. Our findings can be helpful for a better understanding of sequence-dependent mutability. Further, detailed structural characterization of mismatches can serve for designing anti-cancer drugs targeting mismatched base pairs.

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Section: Methodsmentioning

confidence: 99%

Importance of base-pair opening for mismatch recognition

Bouchal

Durník

Illík

et al. 2020

Nucleic Acids Research

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“…On the other hand, molecular dynamics models, fully atomistic [28][29][30][31][32][33][34][35][36][37][38][39][40] or coarse-grained (mesoscopic), [41][42][43][44][45][46] provide different insight into the mechanics of the nucleic acids. The specific choice of the level of granularity of the models depends on the problem at hand.…”

Section: Introductionmentioning

confidence: 99%

Stretching of long double-stranded DNA and RNA described by the same model

Afanasyev

Onufriev

2022

Preprint

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We propose a bead-spring model that accurately reproduces a variety of experimental force-extension curves of long double-stranded DNA and RNA, including torsionally constrained and unconstrained DNA, and negatively supercoiled DNA. A key feature of the model is a specific non-convex energy function of the spring. We provide an algorithm for obtaining five required parameters of the model from experimental force-extension curves. In the plateau region of the force-extension curves, our molecular dynamics simulations show that the polymer separates into a mix of weakly and strongly stretched states without forming macroscopically distinct phases.

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“…36 These refinements have become an essential process in order to obtain accurate results in the microsecond timescale. Comparative studies of the common nucleic acid force fields have been performed to evaluate the mesoscale properties of DNA, 37 and to reproduce NMR structures of the Drew-Dickerson dodecamer (DDD) system. 35 Minhas et al found the CHARMM27 model to have the most stable trajectories and best agreement to the experimental data for describing the mesoscale properties of multimicrosecond simulations of long DNA fragments (40 base pairs) in a cubic solvation box of TIP3P water.…”

Section: Introductionmentioning

confidence: 99%

“…While the study revealed both AMBER family models to have good agreement with the experimental data, the CHARMM36 model had unstable trajectories in the microsecond timescale and produced irreversible fluctuations. 37 Whether the choice of force field can affect the pathways and free energy landscape of the conformational transition between the WC and HG base pairing forms is not yet clear.…”

Section: Introductionmentioning

confidence: 99%

“…In the current work, we address this question by comparing the underlying free energy landscape of WC to HG transition, and the energetic and entropic stabilization of individual base pairing states for the four different force fields: CHARMM27, CHARMM36, AMBERbsc0 and AMBERbsc1. Although newer nucleic acid force fields are available, 35,38 our choice of force fields was inspired by the recent comparative study by Minhas et al, 37 and molecular dynamics studies of HG base pair formation in the literature. The free energy surface and associated thermodynamic properties of the HG conformation of the A16–T9 base pair in A 6 -DNA 3 are explored through enhanced sampling simulation using the advanced meta-eABF approach.…”

Section: Introductionmentioning

confidence: 99%

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Force Field Dependent DNA Breathing Dynamics: A Case Study of Hoogsteen Base Pairing in A6-DNA

Stone

Ray

Andricioaei

2022

Preprint

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The Hoogsteen (HG) base pairing (bp) conformation, commonly observed in damaged and mutated DNA helix, facilitates DNA repair mechanism and DNA recognition by proteins and small molecules. The free energy difference of HG and Watson-Crick (WC) base pairs has been computed in previous computational studies. But, the mechanism of the conformational transition is not well understood. A detailed understanding of the process of WC to HG base pair transition can provide deeper understanding of DNA repair and recognition. In an earlier study, we explored the free energy landscape for this process using extensive computer simulation with CHARMM36 force field for the nucleic acid. In this work, we study the impact of force field models in describing the WC to HG base pairing transition using the meta-eABF enhanced sampling, quasi-harmonic entropy calculation, and non-bonded energy analysis. The secondary structures of the both base pairing forms and the topology of the free energy landscapes were consistent over different force field models, although the relative free energy, entropy and the interaction energies tend to vary. The relative stability of WC and HG conformation is dictated by a delicate balance between the enthalpic stabilization and the reduced entropy of the structurally rigid HG structure. These findings provide a holistic view on the impact of force fields on the DNA base pair dynamics leading to the formation of HG conformation and will facilitate future computational investigations of DNA repair and recognition mechanism in physiologically relevant conditions.

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Modeling DNA Flexibility: Comparison of Force Fields from Atomistic to Multiscale Levels

Cited by 41 publications

References 70 publications

Importance of base-pair opening for mismatch recognition

Importance of base-pair opening for mismatch recognition

Stretching of long double-stranded DNA and RNA described by the same model

Force Field Dependent DNA Breathing Dynamics: A Case Study of Hoogsteen Base Pairing in A6-DNA

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