We introduce an extended version of oxDNA, a coarse-grained model of deoxyribonucleic acid (DNA) designed to capture the thermodynamic, structural, and mechanical properties of single-and double-stranded DNA. By including explicit major and minor grooves and by slightly modifying the coaxial stacking and backbone-backbone interactions, we improve the ability of the model to treat large (kilobase-pair) structures, such as DNA origami, which are sensitive to these geometric features. Further, we extend the model, which was previously parameterised to just one salt concentration ([Na + ] = 0.5M), so that it can be used for a range of salt concentrations including those corresponding to physiological conditions. Finally, we use new experimental data to parameterise the oxDNA potential so that consecutive adenine bases stack with a different strength to consecutive thymine bases, a feature which allows a more accurate treatment of systems where the flexibility of single-stranded regions is important. We illustrate the new possibilities opened up by the updated model, oxDNA2, by presenting results from simulations of the structure of large DNA objects and by using the model to investigate some salt-dependent properties of DNA. C 2015 AIP Publishing LLC. [http://dx

We give evidence of a clear structural signature of the glass transition, in terms of a static correlation length with the same dependence on the system size, which is typical of critical phenomena. Our approach is to introduce an external, static perturbation to extract the structural information from the system's response. In particular, we consider the transformation behavior of the local minima of the underlying potential energy landscape (inherent structures), under a static deformation. The finite-size scaling analysis of our numerical results indicate that the correlation length diverges at a temperature Tc, below the temperatures where the system can be equilibrated. Our numerical results are consistent with random first order theory, which predicts such a divergence with a critical exponent ν=2/3 at the Kauzmann temperature, where the extrapolated configurational entropy vanishes.

The rupture of double-stranded DNA under stress is a key process in biophysics and nanotechnology. In this article, we consider the shear-induced rupture of short DNA duplexes, a system that has been given new importance by recently designed force sensors and nanotechnological devices. We argue that rupture must be understood as an activated process, where the duplex state is metastable and the strands will separate in a finite time that depends on the duplex length and the force applied. Thus, the critical shearing force required to rupture a duplex depends strongly on the time scale of observation. We use simple models of DNA to show that this approach naturally captures the observed dependence of the force required to rupture a duplex within a given time on duplex length. In particular, this critical force is zero for the shortest duplexes, before rising sharply and then plateauing in the long length limit. The prevailing approach, based on identifying when the presence of each additional base pair within the duplex is thermodynamically unfavorable rather than allowing for metastability, does not predict a time-scale-dependent critical force and does not naturally incorporate a critical force of zero for the shortest duplexes. We demonstrate that our findings have important consequences for the behavior of a new force-sensing nanodevice, which operates in a mixed mode that interpolates between shearing and unzipping. At a fixed time scale and duplex length, the critical force exhibits a sigmoidal dependence on the fraction of the duplex that is subject to shearing.

The formation of quasi-spherical cages from protein building blocks is a remarkable self-assembly process in many natural systems, where a small number of elementary building blocks are assembled to build a highly symmetric icosahedral cage. In turn, this has inspired synthetic biologists to design de novo protein cages. We use simple models, on multiple scales, to investigate the self-assembly of a spherical cage, focusing on the regularity of the packing of protein-like objects on the surface. Using building blocks, which are able to pack with icosahedral symmetry, we examine how stable these highly symmetric structures are to perturbations that may arise from the interplay between flexibility of the interacting blocks and entropic effects. We find that, in the presence of those perturbations, icosahedral packing is not the most stable arrangement for a wide range of parameters; rather disordered structures are found to be the most stable. Our results suggest that () many designed, or even natural, protein cages may not be regular in the presence of those perturbations and () optimizing those flexibilities can be a possible design strategy to obtain regular synthetic cages with full control over their surface properties.

We propose deformations of inherent structures as a suitable tool for detecting structural changes underlying the onset of cooperativity in supercooled liquids. The non-affine displacement (NAD) field resulting from the applied deformation shows characteristic differences between the high temperature liquid and supercooled state, which are typically observed in dynamic quantities. The average magnitude of the NAD is very sensitive to temperature changes in the supercooled regime and is found to be strongly correlated with the inherent structure energy. In addition, the NAD field is characterized by a correlation length that increases upon lowering the temperature towards the supercooled regime.

DNA-binding proteins utilise different recognition mechanisms to locate their DNA targets; some proteins recognise specific DNA sequences, while others interact with specific DNA structures. While sequence-specific DNA binding has been studied extensively, structure-specific recognition mechanisms remain unclear. Here, we study structure-specific DNA recognition by examining the structure and dynamics of DNA polymerase I Klenow Fragment (Pol) substrates both alone and in DNA–Pol complexes. Using a docking approach based on a network of 73 distances collected using single-molecule FRET, we determined a novel solution structure of the single-nucleotide-gapped DNA–Pol binary complex. The structure resembled existing crystal structures with regards to the downstream primer-template DNA substrate, and revealed a previously unobserved sharp bend (∼120°) in the DNA substrate; this pronounced bend was present in living cells. MD simulations and single-molecule assays also revealed that 4–5 nt of downstream gap-proximal DNA are unwound in the binary complex. Further, experiments and coarse-grained modelling showed the substrate alone frequently adopts bent conformations with 1–2 nt fraying around the gap, suggesting a mechanism wherein Pol recognises a pre-bent, partially-melted conformation of gapped DNA. We propose a general mechanism for substrate recognition by structure-specific enzymes driven by protein sensing of the conformational dynamics of their DNA substrates.

We study the dynamics of DNA hairpin formation using oxDNA, a nucleotide-level coarse-grained model of DNA. In particular, we explore the effects of the loop stacking interactions and non-native base pairing on the hairpin closing times. We find a non-monotonic variation of the hairpin closing time with temperature, in agreement with the experimental work of Wallace et al. [Proc. Nat. Acad. Sci. USA 2001, 98, 5584-5589]. The hairpin closing process involves the formation of an initial nucleus of one or two bonds between the stems followed by a rapid zippering of the stem. At high temperatures, typically above the hairpin melting temperature, an effective negative activation enthalpy is observed because the nucleus has a lower enthalpy than the open state. By contrast, at low temperatures, the activation enthalpy becomes positive mainly due to the increasing energetic cost of bending a loop that becomes increasingly highly stacked as the temperature decreases. We show that stacking must be very strong to induce this experimentally observed behavior, and that the existence of just a few weak stacking points along the loop can substantially suppress it. Non-native base pairs are observed to have only a small effect, slightly accelerating hairpin formation.

We find that the hierarchical organization of the potential energy landscape in a model supercooled liquid can be related to a change in the spatial distribution of soft normal modes. For groups of nearby minima, between which fast relaxation processes typically occur, the localization of the soft modes is very similar. The spatial distribution of soft regions changes, instead, for minima between which transitions relevant to structural relaxation occur. This may be the reason why the soft modes are able to predict spatial heterogeneities in the dynamics. Nevertheless, the very softest modes are only weakly correlated with dynamical heterogeneities and instead show higher statistical overlap with regions in the local minima that would undergo nonaffine rearrangements if subjected to a shear deformation. This feature of the supercooled liquid is reminiscent of the behavior of nonaffine deformations in amorphous solids, where the very softest modes identify the loci of plastic instabilities.