No Arabic abstract
Double-stranded DNA `overstretches at a pulling force of about 65 pN, increasing in length by a factor of 1.7. The nature of the overstretched state is unknown, despite its considerable importance for DNAs biological function and technological application. Overstretching is thought by some to be a force-induced denaturation, and by others to consist of a transition to an elongated, hybridized state called S-DNA. Within a statistical mechanical model we consider the effect upon overstretching of extreme sequence heterogeneity. `Chimeric sequences possessing halves of markedly different AT composition elongate under fixed external conditions via distinct, spatially segregated transitions. The corresponding force-extension data display two plateaux at forces whose difference varies with pulling rate in a manner that depends qualitatively upon whether the hybridized S-form is accessible. This observation implies a test for S-DNA that could be performed in experiment. Our results suggest that qualitatively different, spatially segregated conformational transitions can occur at a single thermodynamic state within single molecules of DNA.
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 $C_text{eff}$ 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 non-perturbative 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 non-perturbative 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.
We investigate the translocation of a single stranded DNA through a pore which fluctuates between two conformations, using coupled master equations. The probability density function of the first passage times (FPT) of the translocation process is calculated, displaying a triple, double or mono peaked behavior, depending on the interconversion rates between the conformations, the applied electric field, and the initial conditions. The cumulative probability function of the FPT, in a field-free environment, is shown to have two regimes, characterized by fast and slow timescales. An analytical expression for the mean first passage time of the translocation process is derived, and provides, in addition to the interconversion rates, an extensive characterization of the translocation process. Relationships to experimental observations are discussed.
When DNA molecules are heated they denature. This occurs locally so that loops of molten single DNA strands form, connected by intact double-stranded DNA pieces. The properties of this melting transition have been intensively investigated. Recently there has been a surge of interest in this question, caused by experiments determining the properties of partially bound DNA confined to nanochannels. But how does such confinement affect the melting transition? To answer this question we introduce, and solve a model predicting how confinement affects the melting transition for a simple model system by first disregarding the effect of self-avoidance. We find that the transition is smoother for narrower channels. By means of Monte-Carlo simulations we then show that a model incorporating self-avoidance shows qualitatively the same behaviour and that the effect of confinement is stronger than in the ideal case.
We propose a physically-realisable biochemical device that is coupled to a biochemical reservoir of mutual information, fuel molecules and a chemical bath. Mutual information allows work to be done on the bath even when the fuel molecules appear to be in equilibrium; alternatively, mutual information can be created by driving from the fuel or the bath. The system exhibits diverse behaviour, including a regime in which the information, despite increasing during the reaction, enhances the extracted work. We further demonstrate that a modified device can function without the need for external manipulation, eliminating the need for a complex and potentially costly control.
An exactly solvable model based on the topology of a protein native state is applied to identify bottlenecks and key-sites for the folding of HIV-1 Protease. The predicted sites are found to correlate well with clinical data on resistance to FDA-approved drugs. It has been observed that the effects of drug therapy are to induce multiple mutations on the protease. The sites where such mutations occur correlate well with those involved in folding bottlenecks identified through the deterministic procedure proposed in this study. The high statistical significance of the observed correlations suggests that the approach may be promisingly used in conjunction with traditional techniques to identify candidate locations for drug attacks.