SerraNA: a program to determine nucleic acids elasticity from simulation data

Velasco-Berrelleza, Victor; Burman, Matthew; Shepherd, Jack W; Leake, Mark C.; Golestanian, Ramin; Noy, Agnes

doi:10.1039/d0cp02713h

Cited by 29 publications

(57 citation statements)

References 89 publications

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“…With increasing improvements in population-scale human variation data, such as the Genome Aggregation Database (38), and predictive modeling to derive the structure of arbitrary DNA sequences (18)(19)(20)(21)(22)39), our study opens up new possibilities to mechanistically understand mutation rate variations in the human genome. In future studies, we may be able to use broader (9-mer) local contexts for predicting mutation rates, which we failed to do in our current study due to limitations from the 1000 Genomes dataset.…”

Section: Discussionmentioning

confidence: 99%

Mutation Rate Variations in the Human Genome are Encoded in DNA Shape

Liu

Samee

2021

Preprint

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Single nucleotide mutation rates have critical implications for human evolution and genetic diseases. Accurate modeling of these mutation rates has long remained an open problem since the rates vary substantially across the human genome. A recent model, however, explained much of the variation by considering higher order nucleotide interactions in the local (7-mer) sequence context around mutated nucleotides. Despite this model’s predictive value, we still lack a clear understanding of the biophysical mechanisms underlying the variations in genome-wide mutation rates. DNA shape features are geometric measurements of DNA structural properties, such as helical twist and tilt, and are known to capture information on interactions between neighboring nucleotides within a local context. Motivated by this characteristic of DNA shape features, we used them to model mutation rates in the human genome. These DNA shape feature based models improved both the accuracy (up to 14%) and the interpretability over the current nucleotide sequence-based models. The models also discovered the specific shape features that capture the most variability in mutation rates, and distinguished between the most and the least mutated sequence contexts, thus characterizing mutation promoting properties of the genomic DNA. To our knowledge, this is the first attempt that demonstrates the structural underpinnings of nucleotide mutations in the human genome and lays the groundwork for future studies to incorporate DNA shape information in modeling genetic variations.

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Section: Discussionmentioning

confidence: 99%

Mutation Rate Variations in the Human Genome are Encoded in DNA Shape

Liu

Samee

2021

Preprint

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“…This technique probes the torsional elasticity by tracing the twist fluctuations of the ends of stretched DNA molecules of several kilobases length. The recent atomistic simulation study by Velasco-Berreleza et al [8] found a similarly strong length-dependence of the torsional fluctuations, although their asymptotic estimate indicates l T /2 ≈ 90 nm. We note here that l T at all length scales is not only determined by the twist stiffness C q , but also by other stiffnesses.…”

Section: B All-atommentioning

confidence: 93%

“…6. This strong length scale dependence of the torsional elasticity can potentially explain the divergence between estimates obtained with different experimental methods [8]. Studies that employ local probing methods find systematically lower stiffnesses as compared to studies in which larger length scales are considered, as is the case for magnetic tweezers (for a list of different estimates and methods used see supplemental of Ref.…”

Section: B Length Dependence Of Persistence Lengthsmentioning

confidence: 99%

“…Computer simulations have been playing an increasingly important role in understanding these properties. Depending on the length scale relevant to the particular issue at hand and the level of detail required, simulations of either atomistic [2][3][4][5][6][7][8] or coarse-grained resolution [9][10][11][12][13][14][15][16][17][18][19][20][21] can be employed. At sufficiently long length scales the mechanical response of DNA is well described by continuous elastic models, such as the Twistable Wormlike Chain (TWLC), which neglects sequence dependent effects [22].…”

Section: Introductionmentioning

confidence: 99%

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Length-scale-dependent elasticity in DNA from coarse-grained and all-atom models

et al. 2021

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We investigate the influence of non-local couplings on the torsional and bending elasticities of DNA. Such couplings have been observed in the past by several simulation studies. Here, we use a description of DNA conformations based on the variables tilt, roll and twist. Our analysis of both coarse-grained (oxDNA) and all-atom models indicates that these share strikingly similar features: there are strong off-site couplings for tilt-tilt and twist-twist, while they are much weaker in the roll-roll case. By developing an analytical framework to estimate bending and torsional persistence lengths in non-local DNA models, we show how off-site interactions generate a length scale dependent elasticity. Based on the simulation generated elasticity data the theory predicts a significant length scale dependent effect on torsional fluctuations, but only a modest effect on bending fluctuations. These results are in agreement with experiments probing DNA mechanics from single base pair to kilobase pair scales.

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“…This mechanism, thereby, constructs a mechanical “switch”, since the ultimate structural configuration can switch between different states in a mechanically dependent manner. The formation of such a sharp bend in one of these observed states is impossible to achieve in naked DNA, even for the most curved sequences (62, 63) unless base stacking and complementary hydrogen-bond pairing are disrupted on the double helix generating kinks or melting bubbles (36).…”

Section: Discussionmentioning

confidence: 99%

Integration host factor bends and bridges DNA in a multiplicity of binding modes with varying specificity

Yoshua

Watson

Howard

et al. 2020

Preprint

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Nucleoid-associated proteins perform crucial roles in compacting prokaryotic DNA, but how they generate higher-order nucleoprotein structures by perturbing DNA topology is unclear.Integration host factor, IHF, is a key nucleoid-associated protein in bacteria, creating sharp bends in DNA. We show that the IHF-DNA complex is more elaborate than a simple twostep model previously suggested and also provide structural insights about its multimodal nature. Using atomic force microscopy and molecular dynamics simulations we find three topological modes in roughly equal proportions: "associated" (73˚), "half-wrapped" (107˚) and "fully-wrapped" (147˚), with only the latter occurring with sequence specificity. DNA bridging is seen not only with high IHF concentrations but also with densely packed binding sites, with simulations showing this occurs through another binding mode that does not depend on sequence. We present a model of these states and propose a crucial biological role for these observed behaviors.

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SerraNA: a program to determine nucleic acids elasticity from simulation data

Abstract: The resistance of DNA to stretch, twist and bend is broadly well estimated by experiments and is important for gene regulation and chromosome packing. However, their sequence-dependence and how bulk...

Cited by 29 publications

References 89 publications

Mutation Rate Variations in the Human Genome are Encoded in DNA Shape

Mutation Rate Variations in the Human Genome are Encoded in DNA Shape

Length-scale-dependent elasticity in DNA from coarse-grained and all-atom models

Integration host factor bends and bridges DNA in a multiplicity of binding modes with varying specificity

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