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We investigate the Rubinstein-Duke model for polymer reptation by means of density-matrix renormalization group techniques both in the absence and presence of a driving field. In the former case the renewal time r and the diffusion coefficient D are calculated for chains up to N = 150 reptons and their scaling behavior in N is analyzed. Both quantities scale as powers of N: τ∼N[sup z] and D ∼ 1/N[sup χ] with the asymptotic exponents z = 3 and x = 2, in agreement with the reptation theory. For an intermediate range of lengths, however, the data are well fitted by some effective exponents whose values are quite sensitive to the dynamics of the end reptons. We find 2.7

Coarse-grained models have emerged as valuable tools to simulate long DNA molecules while maintaining computational efficiency. These models aim at preserving interactions among coarse-grained variables in a manner that mirrors the underlying atomistic description. We explore here a method for testing coarse-grained vs all-atom models using stiffness matrices in Fourier space (q-stiffnesses), which are particularly suited to probe DNA elasticity at different length scales. We focus on a class of coarse-grained rigid base DNA models known as cgDNA and its most recent version, cgDNA+. Our analysis shows that while cgDNA+ closely follows the q-stiffnesses of the all-atom model, the original cgDNA shows some deviations for twist and bending variables, which are rather strong in the q → 0 (long length scale) limit. The consequence is that while both cgDNA and cgDNA+ give a suitable description of local elastic behavior, the former misses some effects that manifest themselves at longer length scales. In particular, cgDNA performs poorly on twist stiffness, with a value much lower than expected for long DNA molecules. Conversely, the all-atom and cgDNA+ twist are strongly length scale dependent: DNA is torsionally soft at a few base pair distances but becomes more rigid at distances of a few dozen base pairs. Our analysis shows that the bending persistence length in all-atom and cgDNA+ is somewhat overestimated. [ABSTRACT FROM AUTHOR]

Abstract: We consider mixtures of two DNA sequences t and t′ differing by a single nucleotide, which are analyzed by an Agilent custom DNA microarray. In particular we focus on the case in which t, the “wild type”, is predominantly abundant and t′ the “mutant” is at very low concentrations compared to t. We show that by using appropriately designed arrays it is possible to accurately quantify the presence of t′ even at low relative concentrations (≈1%). The detection method is based on thermodynamic models of DNA hybridisation and on the analysis of a large number of hybridisation intensities from probes containing one or two mismatches with respect to t and t′. [ABSTRACT FROM AUTHOR]

Abstract: We analyze a series of publicly available controlled experiments (Latin square) on Affymetrix high-density oligonucleotide microarrays using a simple physical model of the hybridization process. We plot for each gene the signal intensity vs. the hybridization free energy of RNA/DNA duplexes in solution, for perfect matching and mismatching probes. Both values tend to align on a single master curve in good agreement with Langmuir adsorption theory, provided one takes into account the decrease of the effective target concentration due to target–target hybridization in solution. We give an example of a deviation from the expected thermodynamical behavior for the probe set 1091_at due to annotation problems, i.e., the surface-bound probe is not the exact complement of the target RNA sequence, because of errors present in public databases at the time when the array was designed. We show that the parametrization of the experimental data with RNA/DNA free energy improves the quality of the fits and enhances the stability of the fitting parameters compared to previous studies. [Copyright &y& Elsevier]

By combining analytical results and simulations of various coarse-grained models, we investigate the minimal energy shape of DNA minicircles which are torsionally constrained by an imposed over or undertwist. We show that twist-bend coupling, a cross interaction term discussed in the recent DNA literature, induces minimal energy shapes with a periodic alternation of parts with high and low curvature resembling rounded polygons. We briefly discuss the possible experimental relevance of these findings. We finally show that the twist and bending energies of minicircles are governed by renormalized stiffness constants, rather than the bare ones. This has important consequences for the analysis of experiments involving circular DNA meant to determine DNA elastic constants. [ABSTRACT FROM AUTHOR]

Mechanical properties of nucleic acids play an important role in many biological processes that often involve physical deformations of these molecules. At sufficiently long length scales (say, above ∼ 20 − 30 base pairs), the mechanics of DNA and RNA double helices is described by a homogeneous Twistable Wormlike Chain (TWLC), a semiflexible polymer model characterized by twist and bending stiffnesses. At shorter scales, this model breaks down for two reasons: the elastic properties become sequence-dependent and the mechanical deformations at distal sites get coupled. We discuss in this paper the origin of the latter effect using the framework of a non-local Twistable Wormlike Chain (nlTWLC). We show, by comparing all-atom simulations data for DNA and RNA double helices, that the non-local couplings are of very similar nature in these two molecules: couplings between distal sites are strong for tilt and twist degrees of freedom and weak for roll. We introduce and analyze a simple double-stranded polymer model that clarifies the origin of this universal distal couplings behavior. In this model, referred to as the ladder model, a nlTWLC description emerges from the coarsening of local (atomic) degrees of freedom into angular variables that describe the twist and bending of the molecule. Different from its local counterpart, the nlTWLC is characterized by a length-scale-dependent elasticity. Our analysis predicts that nucleic acids are mechanically softer at the scale of a few base pairs and are asymptotically stiffer at longer length scales, a behavior that matches experimental data. [ABSTRACT FROM AUTHOR]

As expected, the asymptotic persistence lengths are the same in these two cases, as both converge toward the same HT ht for large m. However, the I B i SB I i sb are determined by the boundary contributions of short segments (small m). This relation holds approximately for the values reported by Wu I et al. i :[1] HT ht nm, I A i = 450 nm, and I B i = 10. Note that expression (2) contains one parameter less than (1), implying that HT ht . [Extracted from the article]

The real‐time identification of protein biomarkers is crucial for the development of point‐of‐care and portable devices. Here, we use a PlyAB biological nanopore to detect haemoglobin (Hb) variants. Adult haemoglobin (HbA) and sickle cell anaemia haemoglobin (HbS), which differ by just one amino acid, were distinguished in a mixture with more than 97 % accuracy based on individual blockades. Foetal Hb, which shows a larger sequence variation, was distinguished with near 100 % accuracy. Continuum and Brownian dynamics simulations revealed that Hb occupies two energy minima, one near the inner constriction and one at the trans entry of the nanopore. Thermal fluctuations, the charge of the protein, and the external bias influence the dynamics of Hb within the nanopore, which in turn generates the unique ionic current signal in the Hb variants. Finally, Hb was counted from blood samples, demonstrating that direct discrimination and quantification of Hb from blood using nanopores, is feasible. [ABSTRACT FROM AUTHOR]

The real‐time identification of protein biomarkers is crucial for the development of point‐of‐care and portable devices. Here, we use a PlyAB biological nanopore to detect haemoglobin (Hb) variants. Adult haemoglobin (HbA) and sickle cell anaemia haemoglobin (HbS), which differ by just one amino acid, were distinguished in a mixture with more than 97 % accuracy based on individual blockades. Foetal Hb, which shows a larger sequence variation, was distinguished with near 100 % accuracy. Continuum and Brownian dynamics simulations revealed that Hb occupies two energy minima, one near the inner constriction and one at the trans entry of the nanopore. Thermal fluctuations, the charge of the protein, and the external bias influence the dynamics of Hb within the nanopore, which in turn generates the unique ionic current signal in the Hb variants. Finally, Hb was counted from blood samples, demonstrating that direct discrimination and quantification of Hb from blood using nanopores, is feasible. [ABSTRACT FROM AUTHOR]

Background: An algorithm for the analysis of Affymetrix Genechips is presented. This algorithm, referred to as the Inverse Langmuir Method (ILM), estimates the binding of transcripts to complementary probes using DNA/RNA hybridization free energies, and the hybridization between partially complementary transcripts in solution using RNA/RNA free energies. The balance between these two competing reactions allows for the translation of background-subtracted intensities into transcript concentrations. Results: To validate the ILM, it is applied to publicly available microarray data from a multi-lab comparison study. Here, microarray experiments are performed on samples which deviate only in few genes. The log2 fold change between these two samples, as obtained from RT-PCR experiments, agrees well with the log2 fold change as obtained with the ILM, indicating that the ILM determines changes in the expression level accurately. We also show that the ILM allows for the identification of outlying probes, as it yields independent concentration estimates per probe. Conclusion: The ILM is robust and offers an interesting alternative to purely statistical algorithms for microarray data analysis. [ABSTRACT FROM AUTHOR]

The simplest model of DNA mechanics describes the double helix as a continuous rod with twist and bend elasticity. Recent work has discussed the relevance of a little-studied coupling G between twisting and bending, known to arise from the groove asymmetry of the DNA double helix. Here the effect of G on the statistical mechanics of long DNA molecules subject to applied forces and torques is investigated. We present a perturbative calculation of the effective torsional stiffness Ceff for small twist-bend coupling. We find that the "bare" G is "screened" by thermal fluctuations, in the sense that the low-force, long-molecule effective free energy is that of a model with G=0 but with long-wavelength bending and twisting rigidities that are shifted by G-dependent amounts. Using results for torsional and bending rigidities for freely fluctuating DNA, we show how our perturbative results can be extended to a nonperturbative regime. These results are in excellent agreement with numerical calculations for Monte Carlo "triad" and molecular dynamics "oxDNA" models, characterized by different degrees of coarse graining, validating the perturbative and nonperturbative analyses. While our theory is in generally good quantitative agreement with experiment, the predicted torsional stiffness does systematically deviate from experimental data, suggesting that there are as-yet-uncharacterized aspects of DNA twisting-stretching mechanics relevant to low-force, long-molecule mechanical response, which are not captured by widely used coarse-grained models. [ABSTRACT FROM AUTHOR]

Background: Affymetrix Genechips are characterized by probe pairs, a perfect match (PM) and a mismatch (MM) probe differing by a single nucleotide. Most of the data preprocessing algorithms neglect MM signals, as it was shown that MMs cannot be used as estimators of the non-specific hybridization as originally proposed by Affymetrix. The aim of this paper is to study in detail on a large number of experiments the behavior of the average PM/MM ratio. This is taken as an indicator of the quality of the hybridization and, when compared between different chip series, of the quality of the chip design. Results: About 250 different GeneChip hybridizations performed at the VIB Microarray Facility for Homo sapiens, Drosophila melanogaster, and Arabidopsis thaliana were analyzed. The investigation of such a large set of data from the same source minimizes systematic experimental variations that may arise from differences in protocols or from different laboratories. The PM/MM ratios are derived theoretically from thermodynamic laws and a link is made with the sequence of PM and MM probe, more specifically with their central nucleotide triplets. Conclusion: The PM/MM ratios subdivided according to the different central nucleotides triplets follow qualitatively those deduced from the hybridization free energies in solution. It is shown also that the PM and MM histograms are related by a simple scale transformation, in agreement with what is to be expected from hybridization thermodynamics. Different quantitative behavior is observed on the different chip organisms analyzed, suggesting that some organism chips have superior probe design compared to others. [ABSTRACT FROM AUTHOR]

Recent work indicates that twist-bend coupling plays an important role in DNA micromechanics. Here we investigate its effect on bent DNA. We provide an analytical solution of the minimum-energy shape of circular DNA, showing that twist-bend coupling induces sinusoidal twist waves. This solution is in excellent agreement with both coarse-grained simulations of minicircles and nucleosomal DNA data, which is bent and wrapped around histone proteins in a superhelical conformation. Our analysis shows that the observed twist oscillation in nucleosomal DNA, so far attributed to the interaction with the histone proteins, is an intrinsic feature of free bent DNA, and should be observable in other protein-DNA complexes. [ABSTRACT FROM AUTHOR]

Recent magnetic tweezers experiments have reported systematic deviations of the twist response of double-stranded DNA from the predictions of the twistable wormlike chain model. Here we show, by means of analytical results and computer simulations, that these discrepancies can be resolved if a coupling between twist and bend is introduced. We obtain an estimate of 40 ± 10 nm for the twist-bend coupling constant. Our simulations are in good agreement with high-resolution, magnetic-tweezers torque data. Although the existence of twist-bend coupling was predicted long ago [J. Marko and E. Siggia, Macromolecules 27, 981 (1994)], its effects on the mechanical properties of DNA have been so far largely unexplored. We expect that this coupling plays an important role in several aspects of DNA statics and dynamics. [ABSTRACT FROM AUTHOR]

Review: 92 refs. [ABSTRACT FROM AUTHOR]