Understanding the mechanical response of double-stranded DNA and RNA under constant stretching forces using all-atom molecular dynamics

Marín-González, Alberto; Vilhena, J. G.; Pérez, Rúben; Moreno‐Herrero, Fernando

doi:10.1073/pnas.1705642114

Cited by 82 publications

(166 citation statements)

References 46 publications

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“…The calculated torsional modulus for all oligomers shows a crossover from the relatively soft value of around 30-60 nm at the single base-pair level to a large-scale asymptotic value between 90 and 100 nm (see Table 1), which is in agreement with previous study. 25 While softer values at short length scales are consistent with fluorescence polarization anisotropy measurements, 58,59 small-angle X-ray scattering (SAXS), 31 analysis of crystallographic DNA structures 29 and many calculations from MD, 21,26,30 stiffer magnitudes concur with single-molecule experiments 8,13,14 and other modelling estimations 19,60,61 at longer length scales. Values calculated for the whole segment also fall within the long-scale range between 90-100 nm (see Table 1), achieving an overall good convergence on the microsecond-long trajectories ( Figure S1) Persistence length.…”

Section: Resultssupporting

confidence: 60%

“…16,17 In addition, it has been very difficult to identify the mechanisms through which some short sequence motifs, like A-tracts, originate extraordinary bending. 18 On these matters, molecular dynamics (MD) simulations at atomic resolution have become an impressive source of new important information, 19 that have provided (i) a systematic analysis of elasticity at the dinucleotide levels, 20,21 (ii) an evaluation of the influence of nearest flanking basepairs up to the our knowledge, there is no other program that estimates bulk flexibility constants from ensembles obtained by numerical simulations and that uncovers systematically how these properties emerge from local fluctuations. We also believe that for the first time, dependence of elasticity on sequence is exhaustive evaluated in this paper, particularly at the tetranucleotide level thanks to analysing the ABC trajectory database.…”

Section: Introductionmentioning

confidence: 99%

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

Velasco-Berrelleza

Burman

Shepherd

et al. 2020

Preprint

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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 sequencedependence and how bulk elastic constants emerge from local fluctuations is less understood.Here, we present SerraNA, which is an open software that infers elastic parameters of doublestranded nucleic acids from bp length up to the whole molecule using ensembles from numerical simulations. Estimations of bulk elastic constants are in general agreement with experiments, although the static persistence length and stretch modulus parameters are more challenging to calculate due to DNA chirality and vibrations at the ends. The program also reveals that a soft persistence length is built up from local periodic bending angles in phase with 1 the DNA helicoidal shape. The whole set of 136 tetra-bp combinations present big differences in all elastic constants of over 200% demonstrating the importance of sequence. SerraNA is a tool to be applied in the next generation of interdisciplinary investigations to further understand what determines the elasticity of DNA. tetranucleotide level 22,23 and, among others, (iii) an explanation of contradictory stiffness data on A-tracts. 24 On a more coarse-grained level, Monte Carlo (MC) simulations have found an average persistence length of 53 nm with a standard deviation of 4 nm, most of the variability being originated at the level of static curvature, with dynamic persistence length fluctuating around 61 ± 1 nm.Previously, we designed the Length-Dependent Elastic Model (LDEM) for describing how bulk elastic properties emerge from base-pair (bp) fluctuations using the sampling obtained by nucleic acids simulations, 25 and, from this perspective, the model was applied to test the new forcefield Parmbsc1. 26 LDEM consists of an extended version of the algorithm used on the widelyknown 3DNA program 27,28 to geometrically describe two bp separated by an increasing number of nucleotides up to several DNA turns. 25 Bending, torsion and stretch are defined via tilt/roll, twist and distance between ends, respectively, and the associated elastic constants are evaluated by the method of inverse covariance matrix. 20,29,30 Using the LDEM on linear fragments of DNA, we found that the crossover from single bp level to bulk elastic behavior occurs typically within one helical turn of DNA. 25 In terms of torsion elasticity, we observed a transition from dinucleotide values of 30-50 nm to the long-range elastic constants of 90-120 nm broadly in agreement with experimental data. 8,13,14,31 The lengthdependence of stretch modulus followed a non-monotonic behaviour with a stiffening for lengths shorter than a DNA-turn due to the strong base-stacking interactions, followed by stabilization to similar values of force-extension measurements (1100-1500 pN). 11,12 Highly soft stretch modulus measured by SAXS experiments on short oligomers 32 was observed to be caused mainly by end effects. And finally for the persistence length, we f...

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Section: Resultssupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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

Velasco-Berrelleza

Burman

Shepherd

et al. 2020

Preprint

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“…Using constant-force molecular dynamics (MD) simulations [14], we observed that the extension of the DNA changed from one sequence to another for molecules with the same number of base pairs. We performed over 1 μs-long MD simulations of 18 base pair long DNA molecules with benchmark sequences of the form CGCGðNNÞ 5 CGCG, where NN denotes AA, AC, AG, AT, CG, and GG, and computed its average structure at 1 pN force, see Fig.…”

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confidence: 99%

DNA Crookedness Regulates DNA Mechanical Properties at Short Length Scales

et al. 2019

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Sequence-dependent DNA conformation and flexibility play a fundamental role in the specificity of DNA-protein interactions. Here we quantify the DNA crookedness: a sequence-dependent deformation of DNA that consists of periodic bends of the base pair centers chain. Using extensive 100 μs-long, all-atom molecular dynamics simulations, we found that DNA crookedness and its associated flexibility are bijective, which unveils a one-to-one relation between DNA structure and dynamics. This allowed us to build a predictive model to compute the stretch moduli of different DNA sequences from solely their structure. Sequences with very little crookedness show extremely high stretching stiffness and have been previously shown to form unstable nucleosomes and promote gene expression. Interestingly, the crookedness can be tailored by epigenetic modifications, known to affect gene expression. Our results rationalize the idea that the DNA sequence is not only a chemical code, but also a physical one that allows finely regulating its mechanical properties and, possibly, its 3D arrangement inside the cell.

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“…Using constant-force molecular dynamics (MD) simulations (14) we observed that the extension of the DNA changed from one sequence to another for molecules with the same number of base pairs. we observed that the extension of the DNA changed from one sequence to another for molecules with the same number of base pairs.…”

mentioning

confidence: 99%

“…represents an estimation of nucleosome curvature according to (28). b, The computed value of is plotted as a function of the value directly measured from the force-extension curve as done in (14). The stretch modulus was computed from our model for the simulated sequences described above using Eq.…”

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confidence: 99%

DNA crookedness regulates DNA mechanical properties at short length scales

Marín-González

Vilhena

Moreno‐Herrero

et al. 2018

Preprint

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Sequence-dependent DNA conformation and flexibility play a fundamental role in specificity of DNAprotein interactions. Here we quantify the DNA crookedness: a sequence-dependent deformation of DNA that consists on periodic bends of the base pair centers chain. Using molecular dynamics simulations, we found that DNA crookedness and its associated flexibility are bijective: unveiling a one-to-one relation between DNA structure and dynamics. This allowed us to build a predictive model to compute DNA stretching stiffness from solely its structure. Sequences with very little crookedness show extremely high stiffness and have been previously shown to form unstable nucleosomes and promote gene expression. Interestingly, the crookedness can be tailored by epigenetic modifications, known to affect gene expression. Our results rationalize the idea that the DNA sequence is not only a chemical code, but also a physical one that allows to finely regulate its mechanical properties and, possibly, its 3D arrangement inside the cell. MAIN TEXTThe mechanism by which proteins interact with the genome with such extraordinary specificity is still an open question in biology. Since the discovery of the DNA double helix (dsDNA), it became clear the existence of a sequence dependent set of hydrogen bond donors and acceptors that are exposed in the major groove and specifically recognized by certain amino acids. However, there is increasing evidence that this mechanism is far from sufficient. In a number of DNA-protein complexes, DNA adopts a conformation that substantially deviates from the canonical B-form (1-3), suggesting a structural deformation or an exceptional flexibility intrinsic to the DNA sequence. Among the most-studied cases are sequencedependent DNA deformations -A-like structures, kinked base pair steps and A-tracts-that play an important role in transcription regulation (4-7). In parallel, the high sequence-dependent flexibility of DNA is used by several proteins to achieve binding specificity (1,8).However, many aspects of DNA flexibility have so far remained elusive. Indeed, It is not fully understood how a relatively stiff molecule, with a persistence length of P∼50 nm, is able to wrap around a histone octamer of ∼4 nm of radius. Even more intriguing is the fact that some sequences are hardly able to form stable nucleosomes, arguably as a consequence of a distinct conformation or mechanical properties (9, 10). The same question holds for other DNA-protein complexes, in particular, for many repressor systems where a highly bent loop is predicted in the DNA (11). These considerations, supported by recent findings on high bendability of DNA at short-length scales (12, 13) challenge the currently accepted wormlike chain model (WLC) and demand for an accurate description of sequence-dependent DNA flexibility at these scales.Using constant-force molecular dynamics (MD) simulations (14) we observed that the extension of the DNA changed from one sequence to another for molecules with the same number of base pairs. we...

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Understanding the mechanical response of double-stranded DNA and RNA under constant stretching forces using all-atom molecular dynamics

Cited by 82 publications

References 46 publications

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

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

DNA Crookedness Regulates DNA Mechanical Properties at Short Length Scales

DNA crookedness regulates DNA mechanical properties at short length scales

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